FAM134B Regulates Collagen I Processing and Fibrogenesis in Hepatic Stellate Cells

Abstract

Liver fibrosis is driven by the accumulation of scar tissue in response to liver injury. Activated hepatic stellate cells (HSCs) secrete fibrogenic proteins that deposit into the extracellular matrix, leading to fibrosis, cirrhosis, and liver failure. The increased production and secretion of fibrogenic proteins by HSCs results in ER stress, triggering the Unfolded Protein Response (UPR) to manage protein quality control. The UPR is important in regulating HSC activation and fibrogenesis, but the mechanisms driving this regulation are unclear. A key process regulated by the UPR is degradation of misfolded proteins through various pathways, including ER-to-Lysosome-Associated Degradation (ERLAD). ERLAD targets proteins for lysosomal degradation and can involve the recruitment of the autophagosome to engulf portions of the ER, a process termed ER-phagy. While ER-phagy is implicated in collagen degradation, its role in fibrogenesis is unknown. We show that collagen I levels are regulated by autophagy, and this correlates with changes in ER-phagy receptors. Furthermore, TGFβ-mediated activation of HSCs induces ER-phagic flux and expression of ER-phagy receptors FAM134B and CCPG1 in a process dependent on UPR transducer ATF6α. The loss of FAM134B, but not CCPG1, decreases intracellular collagen I protein levels without affecting COL1A1 mRNA levels or procollagen I protein levels in immortalized human HSCs (LX-2 cells). Moreover, FAM134B deletion blocks TGFβ-induced extracellular collagen I deposition despite increased collagen I secreted into the conditioned media. We conclude that FAM134B is pivotal for collagen I deposition during fibrogenesis, and its loss may promote the secretion of misfolded collagen I that cannot be deposited in the extracellular matrix.