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Xia Lin - One of the best experts on this subject based on the ideXlab platform.
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PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1
Science advances, 2016Co-Authors: Weiwen Xiang, Tao Shen, Xia Lin, Qian Zhang, Yao Zhou, Fansen Meng, Yunyun Fan, Mu Xiao, Zongping XiaAbstract:Cytosolic RNA sensing is a prerequisite for initiation of innate immune response against RNA viral pathogens. Signaling through RIG-I (retinoic acid–inducible gene I)–like receptors (RLRs) to TBK1 (Tank-binding kinase 1)/IKKe (IκB kinase e) kinases is transduced by mitochondria-associated MAVS (mitochondrial antiviral signaling protein). However, the precise mechanism of how MAVS-mediated TBK1/IKKe activation is strictly controlled still remains obscure. We reported that protein phosphatase magnesium-dependent 1A (PPM1A; also known as PP2Cα), depending on its catalytic ability, dampened the RLR-IRF3 (interferon regulatory factor 3) axis to silence cytosolic RNA sensing signaling. We demonstrated that PPM1A was an inherent partner of the TBK1/IKKe complex, targeted both MAVS and TBK1/IKKe for dephosphorylation, and thus disrupted MAVS-driven formation of signaling complex. Conversely, a high level of MAVS can dissociate the TBK1/PPM1A complex to override PPM1A-mediated inhibition. Loss of PPM1A through gene ablation in human embryonic kidney 293 cells and mouse primary macrophages enabled robustly enhanced antiviral responses. Consequently, PPM1A−/− mice resisted to RNA virus attack, and transgenic zebrafish expressing PPM1A displayed profoundly increased RNA virus vulnerability. These findings identify PPM1A as the first known phosphatase of MAVS and elucidate the physiological function of PPM1A in antiviral immunity on whole animals.
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PPM1A functions as a smad phosphatase to terminate tgfβ signaling
Cell, 2016Co-Authors: Xia Lin, Yao-yun Liang, Xueyan Duan, Katharine H Wrighton, Jianyin Long, Candi M Davis, Jinrong Wang, Charles F Brunicardi, Yigong Shi, Yeguang ChenAbstract:TGFβ signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGFβ responses are generally mediated through transcriptional functions of Smads. A key step in TGFβ signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGFβ type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGFβ signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2Cα as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGFβ-activated Smad2/3. Ectopic expression of PPM1A abolishes TGFβ-induced antiproliferative and transcriptional responses, whereas depletion of PPM1A enhances TGFβ signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2Cα, through dephosphorylation of Smad2/3, plays a critical role in terminating TGFβ signaling.
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PPM1A dephosphorylates ranbp3 to enable efficient nuclear export of smad2 and smad3
EMBO Reports, 2011Co-Authors: Fangyan Dai, Tao Shen, Xia Lin, Xin-hua FengAbstract:Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
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Erratum: PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3 ((EMBO Reports (2011) doi:10.1038/embor.2011.174)
EMBO reports, 2011Co-Authors: Fangyan Dai, Tao Shen, Xia Lin, Xin-hua FengAbstract:Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
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Phosphatase PPM1A Regulates Phosphorylation of Thr-186 in the Cdk9 T-loop
The Journal of biological chemistry, 2008Co-Authors: Yan Wang, Eugene C. Dow, Yao-yun Liang, Rajesh Ramakrishnan, Hongbing Liu, Tzu-ling Sung, Xia Lin, Andrew P. RiceAbstract:Abstract Cdk9 is the catalytic subunit of a general RNA polymerase II elongation factor known as positive transcription elongation factor b (P-TEFb). The kinase function of P-TEFb requires phosphorylation of Thr-186 in the T-loop of Cdk9 to allow substrates to access the catalytic core of the enzyme. To identify human phosphatases that dephosphorylate the T-loop of Cdk9, we used a Thr-186-phosphospecific antiserum to screen a phosphatase expression library. Overexpression of PPM1A and the related PPM1B greatly reduced Cdk9 T-loop phosphorylation in vivo. PPM1A and Cdk9 appear to associate in vivo as the proteins could be co-immunoprecipitated. The short hairpin RNA depletion of PPM1A resulted in an increase in Cdk9 T-loop phosphorylation. In phosphatase reactions in vitro, purified PPM1A could dephosphorylate Thr-186 both with and without the association of 7SK RNA, a small nuclear RNA that is bound to ∼50% of total cellular P-TEFb. PPM1B only efficiently dephosphorylated Cdk9 Thr-186 in vitro when 7SK RNA was depleted from P-TEFb. Taken together, our data indicate that PPM1A and to some extent PPM1B are important negative regulators of P-TEFb function.
Maria Trojanowska - One of the best experts on this subject based on the ideXlab platform.
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opposite effects of dihydrosphingosine 1 phosphate and sphingosine 1 phosphate on transforming growth factor β smad signaling are mediated through the pten PPM1A dependent pathway
Journal of Biological Chemistry, 2008Co-Authors: Bagrat Kapanadze, Tien Hsu, Maria TrojanowskaAbstract:Transforming growth factor-β (TGF-β) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-β through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-β signaling. In contrast to S1P, dhS1P inhibits TGF-β-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-β signaling. Consequently, overexpression of PTEN abrogates TGF-β-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-β signaling pathways may play an important role in physiological and pathological TGF-β signaling.
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Opposite Effects of Dihydrosphingosine 1-Phosphate and Sphingosine 1-Phosphate on Transforming Growth Factor-β/Smad Signaling Are Mediated through the PTEN/PPM1A-dependent Pathway
The Journal of biological chemistry, 2008Co-Authors: Bagrat Kapanadze, Tien Hsu, Maria TrojanowskaAbstract:Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-beta signaling. In contrast to S1P, dhS1P inhibits TGF-beta-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-beta signaling. Consequently, overexpression of PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-beta signaling pathways may play an important role in physiological and pathological TGF-beta signaling.
Ju Zhou - One of the best experts on this subject based on the ideXlab platform.
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tripartite motif protein 52 trim52 promoted fibrosis in lx 2 cells through PPM1A mediated smad2 3 pathway
Cell Biology International, 2020Co-Authors: Ju Zhou, Qing Lan, Lin Yang, Jing You, Yanmei ZhangAbstract:To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-β (TGF-β), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-β/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-β/Smad pathway.
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Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX-2 cells through PPM1A-mediated Smad2/3 pathway.
Cell biology international, 2019Co-Authors: Ju Zhou, Qing Lan, Lin Yang, Jing You, Yan‐mei ZhangAbstract:To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-β (TGF-β), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-β/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-β/Smad pathway.
Xin-hua Feng - One of the best experts on this subject based on the ideXlab platform.
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PPM1A dephosphorylates ranbp3 to enable efficient nuclear export of smad2 and smad3
EMBO Reports, 2011Co-Authors: Fangyan Dai, Tao Shen, Xia Lin, Xin-hua FengAbstract:Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
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Erratum: PPM1A dephosphorylates RanBP3 to enable efficient nuclear export of Smad2 and Smad3 ((EMBO Reports (2011) doi:10.1038/embor.2011.174)
EMBO reports, 2011Co-Authors: Fangyan Dai, Tao Shen, Xia Lin, Xin-hua FengAbstract:Smad2 and Smad3 (Smad2/3) are essential signal transducers and transcription factors in the canonical transforming growth factor-β (TGF-β) signalling pathway. Active Smad2/3 signalling in the nucleus is terminated by dephosphorylation and subsequent nuclear export of Smad2/3. Here we report that protein phosphatase PPM1A regulates the nuclear export of Smad2/3 through targeting nuclear exporter RanBP3. PPM1A directly interacted with and dephosphorylated RanBP3 at Ser 58 in vitro and in vivo. Consistently, RanBP3 phosphorylation was elevated in PPM1A-null mouse embryonic fibroblasts. Dephosphorylation of RanBP3 at Ser 58 promoted its ability to export Smad2/3 and terminate TGF-β responses. Our findings indicate the critical role of PPM1A in maximizing exporter activity of RanBP3 for efficient termination of canonical TGF-β signalling.
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Expression of PTEN, PPM1A and P-Smad2 in hepatocellular carcinomas and adjacent liver tissues.
World journal of gastroenterology, 2007Co-Authors: Baoju Wang, Xin-hua Feng, Yan Yang, Xi-ping Zhao, Dongliang YangAbstract:AIM: To investigate the expressions of PTEN, PPM1A and P-Smad2 in hepatocellular carcinoma (HCC) and their significance. METHODS: The expressions of PTEN, PPM1A and P-Smad2 in 31 HCC tissues, 25 adjacent liver tissues and 13 non-tumor liver tissues were detected by using Envision immunohistochemical technique. RESULTS: The positive expression (64.52%) and staining intensity (4.19 ± 3.31) of PTEN in the cytoplasm of HCC were significantly lower and weaker than those in the adjacent or non-tumor liver tissues (97.37%, 7.88 ± 0.93; 100%, 7.77 ± 0.93, respectively) (P < 0.05), and its staining intensity in the cytoplasm of HCC, which belongs to Edmondson pathologic grades II-III and above, was also lower than that of gradeIandI-II. Furthermore, its location in the nucleus or cytoplasm of liver cells was negatively correlated with the progression of liver disease (r = -0.339, P = 0.002); most of PPM1A might be only expressed in the nucleus of adjacent liver tissues, non-HCC tissues or Edmondson gradeIandI-II HCC, but it was mainly expressed in the cytoplasm of HCC with Edmondson grade ≥ II, weakly or negatively expressed in the nucleus (P < 0.05), and its location was negatively correlated with the progression of liver disease (r = -0.45, P = 0.0000). P-Smad2, which was mostly located in the nucleus and cytoplasm of gradeIandI-II HCC, surrounding or non-tumor liver tissues, was only in the nucleus of HCC with Edmondson grade II and above (P < 0.001), and its location was positively correlated with the disease progression (r = 0.224, P = 0.016). Spearman correlation analysis revealed that P-Smad2 was significantly negatively correlated with PTEN and PPM1A (r = -0.748, P = 0.000; r = -0.366, P = 0.001, respectively); and PTEN and PPM1A were positively correlated with HCC carcinogenesis (r = 0.428, P = 0.000). CONCLUSION: The aberrant location of expression and staining intensity of PTEN, PPM1A and P-Smad2 in HCC and their relationship might have an impact on the pathogenesis of HCC.
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protein serine threonine phosphatase PPM1A dephosphorylates smad1 in the bone morphogenetic protein signaling pathway
Journal of Biological Chemistry, 2006Co-Authors: Xueyan Duan, Yao-yun Liang, Xin-hua Feng, Xia LinAbstract:Bone morphogenetic proteins (BMPs) are secreted polypeptides belonging to the transforming growth factor-β (TGF-β) superfamily that activates a broad range of biological responses in the metazoan organism. The BMP-initiated signaling pathway is under tight control by processes including regulation of the ligands, the receptors, and the key downstream intracellular effector Smads. A critical point of control in BMP signaling is the phosphorylation of Smad1, Smad5, and Smad8 in their C-terminal SXS motif. Although such phosphorylation, which is mediated by the type I BMP receptor kinases in response to BMP stimulation, is well characterized, biochemical mechanisms underlying Smad dephosphorylation remain to be elucidated. In this study, we have found that PPM1A, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates Smad1 both in vitro and in vivo. Functionally, overexpression of PPM1A abolishes BMP-induced transcriptional responses, whereas RNA interference-mediated knockdown of PPM1A enhances BMP signaling. Collectively, our study suggests that PPM1A plays an important role in controlling BMP signaling through catalyzing Smad dephosphorylation.
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Protein serine/threonine phosphatase PPM1A dephosphorylates Smad1 in the bone morphogenetic protein signaling pathway.
The Journal of biological chemistry, 2006Co-Authors: Xueyan Duan, Yao-yun Liang, Xin-hua Feng, Xia LinAbstract:Bone morphogenetic proteins (BMPs) are secreted polypeptides belonging to the transforming growth factor-β (TGF-β) superfamily that activates a broad range of biological responses in the metazoan organism. The BMP-initiated signaling pathway is under tight control by processes including regulation of the ligands, the receptors, and the key downstream intracellular effector Smads. A critical point of control in BMP signaling is the phosphorylation of Smad1, Smad5, and Smad8 in their C-terminal SXS motif. Although such phosphorylation, which is mediated by the type I BMP receptor kinases in response to BMP stimulation, is well characterized, biochemical mechanisms underlying Smad dephosphorylation remain to be elucidated. In this study, we have found that PPM1A, a metal ion-dependent protein serine/threonine phosphatase, physically interacts with and dephosphorylates Smad1 both in vitro and in vivo. Functionally, overexpression of PPM1A abolishes BMP-induced transcriptional responses, whereas RNA interference-mediated knockdown of PPM1A enhances BMP signaling. Collectively, our study suggests that PPM1A plays an important role in controlling BMP signaling through catalyzing Smad dephosphorylation.
Yan‐mei Zhang - One of the best experts on this subject based on the ideXlab platform.
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Tripartite motif protein 52 (TRIM52) promoted fibrosis in LX-2 cells through PPM1A-mediated Smad2/3 pathway.
Cell biology international, 2019Co-Authors: Ju Zhou, Qing Lan, Lin Yang, Jing You, Yan‐mei ZhangAbstract:To investigate the roles of tripartite motif containing 52 (TRIM52) in human hepatic fibrosis in vitro, human hepatic stellate cell line LX-2 cells were transfected with hepatitis B virus (HBV) replicon to establish HBV-induced fibrosis in LX-2 cells, and then treated with small interfering RNA-mediated knockdown of TRIM52 (siTRIM52). LX-2 cells without HBV replicon transfection were treated with lentiviruses-mediated overexpression of TRIM52 and phosphatase magnesium dependent 1A (PPM1A). Fibrosis response of LX-2 cells were assessed by the production of hydroxyproline (Hyp) and collagen I/III, as well as protein levels of α-smooth muscle actin (α-SMA). PPM1A and phosphorylated (p)-Smad2/3 were measured to assess the mechanism. The correlation between TRIM52 and PPM1A was determined using co-immunoprecipitation, and whether and how TRIM52 regulated the degradation of PPM1A were determined by ubiquitination assay. Our data confirmed HBV-induced fibrogenesis of LX-2 cells, as evidenced by significant increase in Hyp and collagen I/III and α-SMA, which was associated with reduction of PPM1A and elevation of transforming growth factor-β (TGF-β), p-Smad2/3, and p-Smad3L. However, those changes induced by HBV were significantly attenuated with additional siTRIM52 treatment. Similar to HBV, overexpression of TRIM52 exerted promoted effect in the fibrosis of LX-2 cells. Interestingly, TRIM52 induced the fibrogenesis of LX-2 cells and the activation of TGF-β/Smad pathway were significantly reversed by PPM1A overexpression. Furthermore, our data confirmed TRIM52 as a deubiquitinase that influenced the accumulation of PPM1A protein, and subsequently regulated the fibrogenesis of LX-2 cells. TRIM52 was a fibrosis promoter in hepatic fibrosis in vitro, likely through PPM1A-mediated TGF-β/Smad pathway.