The Experts below are selected from a list of 1881 Experts worldwide ranked by ideXlab platform
Santosh Chauhan - One of the best experts on this subject based on the ideXlab platform.
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IRGM Links Autoimmunity to Autophagy
Autophagy, 2020Co-Authors: Parej Nath, Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Kolapalli Srinivas, Santosh ChauhanAbstract:IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
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IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
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IRGM restrains nlrp3 inflammasome activation by mediating its sqstm1 p62 dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, S. K. Das, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
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The Crohn's Disease Risk Factor IRGM Limits NLRP3 Inflammasome Activation by Impeding Its Assembly and by Mediating Its Selective Autophagy.
Molecular cell, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Parej Nath, Gregory A. Taylor, Srinivasa Prasad Kolapalli, S. K. Das, Pradyumna Kumar Sahoo, Ashish Jain, Santosh ChauhanAbstract:Summary Several large-scale genome-wide association studies genetically linked IRGM to Crohn’s disease and other inflammatory disorders in which the IRGM appears to have a protective function. However, the mechanism by which IRGM accomplishes this anti-inflammatory role remains unclear. Here, we reveal that IRGM/IRGM1 is a negative regulator of the NLRP3 inflammasome activation. We show that IRGM expression, which is increased by PAMPs, DAMPs, and microbes, can suppress the pro-inflammatory responses provoked by the same stimuli. IRGM/IRGM1 negatively regulates IL-1β maturation by suppressing the activation of the NLRP3 inflammasome. Mechanistically, we show that IRGM interacts with NLRP3 and ASC and hinders inflammasome assembly by blocking their oligomerization. Further, IRGM mediates selective autophagic degradation of NLRP3 and ASC. By suppressing inflammasome activation, IRGM/IRGM1 protects from pyroptosis and gut inflammation in a Crohn’s disease experimental mouse model. This study for the first time identifies the mechanism by which IRGM is protective against inflammatory disorders.
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Mechanism of action of the tuberculosis and Crohn disease risk factor IRGM in autophagy.
Autophagy, 2016Co-Authors: Santosh Chauhan, Michael A. Mandell, Vojo DereticAbstract:Polymorphisms in the IRGM gene, associated with Crohn disease (CD) and tuberculosis, are among the earliest identified examples documenting the role of autophagy in human disease. Functional studies have shown that IRGM protects against these diseases by modulating autophagy, yet the exact molecular mechanism of IRGM's activity has remained unknown. We have recently elucidated IRGM's mechanism of action. IRGM functions as a platform for assembling, stabilizing, and activating the core autophagic machinery, while at the same time physically coupling it to conventional innate immunity receptors. Exposure to microbial products or bacterial invasion increases IRGM expression, which leads to stabilization of AMPK. Specific protein-protein interactions and post-translational modifications such as ubiquitination of IRGM, lead to a co-assembly with IRGM of the key autophagy regulators ULK1 and BECN1 in their activated forms. IRGM physically interacts with 2 other CD risk factors, ATG16L1 and NOD2, placing these 3 principal players in CD within the same molecular complex. This explains how polymorphisms altering expression or function of any of the 3 factors individually can affect the same process-autophagy. Furthermore, IRGM's interaction with NOD2, and additional pattern recognition receptors such as NOD1, RIG-I, and select TLRs, transduces microbial signals to the core autophagy apparatus. This work solves the long-standing enigma of how IRGM controls autophagy.
Subhash Mehto - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity gene IRGM suppresses cgas sting and rig i mavs signaling to control interferon response
EMBO Reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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IRGM Links Autoimmunity to Autophagy
Autophagy, 2020Co-Authors: Parej Nath, Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Kolapalli Srinivas, Santosh ChauhanAbstract:IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
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Autoimmunity gene IRGM suppresses cGAS‐STING and RIG‐I‐MAVS signaling to control interferon response
EMBO reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways
2019Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, S. K. Das, Pradyumna Kumar Sahoo, Tapas Kumar Nayak, Krushna Chandra MurmuAbstract:Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/815506v1_ufig1.gif" ALT="Figure 1">nView larger version (48K):norg.highwire.dtl.DTLVardef@1d4822org.highwire.dtl.DTLVardef@6aebbcorg.highwire.dtl.DTLVardef@19a9b72org.highwire.dtl.DTLVardef@1539195_HPS_FORMAT_FIGEXP M_FIG C_FIG
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IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
Parej Nath - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity gene IRGM suppresses cgas sting and rig i mavs signaling to control interferon response
EMBO Reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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IRGM Links Autoimmunity to Autophagy
Autophagy, 2020Co-Authors: Parej Nath, Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Kolapalli Srinivas, Santosh ChauhanAbstract:IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
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Autoimmunity gene IRGM suppresses cGAS‐STING and RIG‐I‐MAVS signaling to control interferon response
EMBO reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways
2019Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, S. K. Das, Pradyumna Kumar Sahoo, Tapas Kumar Nayak, Krushna Chandra MurmuAbstract:Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/815506v1_ufig1.gif" ALT="Figure 1">nView larger version (48K):norg.highwire.dtl.DTLVardef@1d4822org.highwire.dtl.DTLVardef@6aebbcorg.highwire.dtl.DTLVardef@19a9b72org.highwire.dtl.DTLVardef@1539195_HPS_FORMAT_FIGEXP M_FIG C_FIG
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IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
Kautilya Kumar Jena - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity gene IRGM suppresses cgas sting and rig i mavs signaling to control interferon response
EMBO Reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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IRGM Links Autoimmunity to Autophagy
Autophagy, 2020Co-Authors: Parej Nath, Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Kolapalli Srinivas, Santosh ChauhanAbstract:IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
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Autoimmunity gene IRGM suppresses cGAS‐STING and RIG‐I‐MAVS signaling to control interferon response
EMBO reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways
2019Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, S. K. Das, Pradyumna Kumar Sahoo, Tapas Kumar Nayak, Krushna Chandra MurmuAbstract:Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/815506v1_ufig1.gif" ALT="Figure 1">nView larger version (48K):norg.highwire.dtl.DTLVardef@1d4822org.highwire.dtl.DTLVardef@6aebbcorg.highwire.dtl.DTLVardef@19a9b72org.highwire.dtl.DTLVardef@1539195_HPS_FORMAT_FIGEXP M_FIG C_FIG
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IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.
Nishant Ranjan Chauhan - One of the best experts on this subject based on the ideXlab platform.
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autoimmunity gene IRGM suppresses cgas sting and rig i mavs signaling to control interferon response
EMBO Reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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IRGM Links Autoimmunity to Autophagy
Autophagy, 2020Co-Authors: Parej Nath, Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Rinku Sahu, Kollori Dhar, Kolapalli Srinivas, Santosh ChauhanAbstract:IRGM is a genetic risk factor for several autoimmune diseases. However, the mechanism of IRGM-mediated protection in autoimmunity remains undetermined. The abnormal activation of type I interferon (IFN) response is one of the significant factors in the pathogenesis of several autoimmune diseases. In our recent study, we showed that IRGM is a master suppressor of the interferon response. We found that the depletion of IRGM results in constitutively activated CGAS-STING1, DDX58/RIG-I-MAVS, and TLR3-TICAM1/TRIF signaling pathways resulting in upregulation of almost all IFN-responsive genes. Mechanistically, IRGM utilizes a two-pronged mechanism to suppress the interferon response. First, it mediates SQSTM1/p62-dependent selective macroautophagy/autophagy of nucleic acid sensor proteins, including CGAS, DDX58/RIG-I, and TLR3. Second, it facilitates the removal of defective mitochondria by mitophagy and avoids a buildup of mito-ROS and mito-damage/danger-associated molecular patterns (DAMPs). Thus, IRGM deficiency results in increased nucleic acid sensors and DAMPs engaging a vicious cycle of aberrant activation of IFN response that is known to occur in systemic autoimmune-like conditions.
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Autoimmunity gene IRGM suppresses cGAS‐STING and RIG‐I‐MAVS signaling to control interferon response
EMBO reports, 2020Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Srinivasa Prasad Kolapalli, S. K. Das, Krushna Chandra Murmu, Ashish JainAbstract:Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid-sensing pathways leading to interferon-stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their p62-dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS-STING and RIG-I-MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.
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Autoimmunity Risk Gene IRGM is a Master Negative Regulator of Interferon Response by Controlling the Activation of cGAS-STING and RIG-I-MAVS Signaling Pathways
2019Co-Authors: Kautilya Kumar Jena, Subhash Mehto, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, S. K. Das, Pradyumna Kumar Sahoo, Tapas Kumar Nayak, Krushna Chandra MurmuAbstract:Activation of type 1 interferon response is extensively connected with the antiviral immunity and pathogenesis of autoimmune diseases. Here, we found that IRGM, whose deficiency is linked with the genesis of several autoimmune disorders, is a master negative regulator of the interferon response. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG-I, and mediates their autophagic degradation to restrain activation of interferon signaling. Further, IRGM maintains mitophagy flux, and its deficiency results in the accumulation of defunct leaky mitochondria that releases cytosolic DAMPs triggering activation of interferon responses via cGAS-STING and RIG-I-MAVS signaling axis. Due to an enduring type 1 IFN response in IRGM-deficient cells and mice, they were intrinsically resistant to infection of the Japanese Encephalitis virus, Herpes Simplex virus, and Chikungunya virus. Altogether, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases. Further, it identifies IRGM as a broad therapeutic target for defense against viruses.nnGraphical AbstractnnO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/815506v1_ufig1.gif" ALT="Figure 1">nView larger version (48K):norg.highwire.dtl.DTLVardef@1d4822org.highwire.dtl.DTLVardef@6aebbcorg.highwire.dtl.DTLVardef@19a9b72org.highwire.dtl.DTLVardef@1539195_HPS_FORMAT_FIGEXP M_FIG C_FIG
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IRGM restrains NLRP3 inflammasome activation by mediating its SQSTM1/p62-dependent selective autophagy
Autophagy, 2019Co-Authors: Subhash Mehto, Swati Chauhan, Kautilya Kumar Jena, Nishant Ranjan Chauhan, Parej Nath, Rinku Sahu, Kollori Dhar, Santosh ChauhanAbstract:IRGM is an established genetic risk factor for Crohn disease (CD) and several other inflammatory disorders. However, the mechanisms employed by IRGM to restrain the inflammation are not known. In our recent study, we showed that IRGM negatively regulates NLRP3 inflammasome activation. IRGM employs 2 parallel approaches to constrain inflammasome activation. First, IRGM directly interacts with NLRP3 and PYCARD/ASC, and mediates their SQSTM1/p62-dependent macroautophagic/autophagic degradation. Second, IRGM impedes inflammasome assembly by blocking the polymerization of NLRP3 and PYCARD. We also found that IRGM suppresses NLRP3-mediated exacerbated outcomes of dextran sodium sulfate (DSS)-induced colitis in a mouse model. Taken together, this study presents evidence that IRGM can directly regulate inflammation and protect from inflammatory diseases.