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Deprecated: Implicit conversion from float 233.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Hepatology 2017 ; 65 (3): 983-98 Nephropedia Template TP
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The UPR mediates fibrogenesis and collagen I secretion through regulating TANGO1 #MMPMID28039913
Maiers JL; Kostallari E; Mushref M; de Assuncao TM; Li H; Huebert RC; Cao S; Malhi H; Shah VH
Hepatology 2017[Mar]; 65 (3): 983-98 PMID28039913show ga
Background/Aims: Fibrogenesis encompasses the deposition of matrix proteins such as collagen I by hepatic stellate cells (HSCs) that culminates in cirrhosis. Fibrogenic signals drive transcription of procollagen I, which enters the endoplasmic reticulum (ER), is trafficked through the secretory pathway, and released to generate extracellular matrix. Alternatively, disruption of procollagen I ER export could activate the unfolded protein response (UPR) and drive HSC apoptosis. Using a siRNA screen, we identified TANGO1 as a potential player in collagen I secretion. We investigated the role of TANGO1 in procollagen I secretion in HSCs and liver fibrogenesis. Methods/Results: Depletion of TANGO1 in HSCs blocked collagen I secretion without affecting other matrix proteins. Disruption of secretion led to procollagen I retention within the ER, induction of the UPR, and HSC apoptosis. In wild-type HSCs, both TANGO1 and the UPR were induced by TGF?. As the UPR upregulates proteins involved in secretion, we studied whether TANGO1 was a target of the UPR. We found that UPR signaling is responsible for upregulating TANGO1 in response to TGF?, and this mechanism is mediated by the transcription factor XBP1. In vivo, murine and human cirrhotic tissue displayed increased TANGO1 mRNA levels. Finally, TANGO1+/? mice displayed less hepatic fibrosis compared to wild-type mice in two separate murine models: CCl4 and BDL. Conclusion: Loss of TANGO1 leads to procollagen I retention in the ER which promotes UPR-mediated HSC apoptosis. TANGO1 regulation during HSC activation occurs through a UPR dependent mechanism that requires the transcription factor XBP-1. Finally, TANGO1 is critical for fibrogenesis through mediating HSC homeostasis. Our work reveals a unique role for TANGO1 and the UPR in facilitating collagen I secretion and fibrogenesis.
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Hepatology 2017 ; 65 (3): 983-98
