FAM134B controls collagen I dynamics in hepatic stellate cell-driven fibrosis.

Abstract

Liver fibrosis is driven by the accumulation of scar tissue in response to injury. Activated hepatic stellate cells (HSCs) secrete fibrogenic proteins that deposit into the extracellular matrix, leading to fibrosis. Increased production of fibrogenic proteins by HSCs leads to endoplasmic reticulum (ER) stress, triggering the unfolded protein response (UPR). The UPR is important in regulating HSC activation and fibrogenesis, but 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 autophagosomes engulfing portions of the ER, termed ER-phagy. ER-phagy is implicated in degradation of misfolded fibrillar collagen, but its role in fibrogenesis is unknown. We show that collagen I levels are posttranslationally regulated by autophagy, and this correlates with ER-phagy receptor expression. Furthermore, activation of HSCs induces ER-phagy flux and expression of ER-phagy receptors, including FAM134B, in a process dependent on UPR transducer ATF6α. Loss of FAM134B decreases intracellular collagen I without affecting COL1A1 mRNA. Moreover, FAM134B deletion blocks transforming growth factor β-induced collagen I deposition despite increased secretion. Together, we show that ER-phagy receptor FAM134B is pivotal for collagen I deposition during fibrogenesis.NEW & NOTEWORTHY We show for the first time that TGFβ-mediated activation of HSCs induces selective autophagy of the endoplasmic reticulum (ER-phagy), through upregulation of ER-phagy receptors and ER-phagic flux. We further show that the unfolded protein response is critical for this effect. Finally, we identify the ER-phagy receptor FAM134B as a critical regulator of collagen I dynamics and fibrogenesis, with loss of FAM134B dysregulating collagen I secretion and deposition.