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

Area of Science:

• Cell Biology
• Molecular Biology
• Gastroenterology

Background:

• Liver fibrosis involves scar tissue accumulation driven by activated hepatic stellate cells (HSCs).
• The Unfolded Protein Response (UPR) regulates HSC activation and fibrogenesis, but its mechanisms are unclear.
• ER-to-Lysosome-Associated Degradation (ERLAD), including ER-phagy, degrades misfolded proteins and is implicated in collagen degradation.

Purpose of the Study:

• To investigate the role of ER-phagy in regulating collagen I deposition during liver fibrogenesis.
• To elucidate the mechanisms by which the UPR controls collagen I levels in HSCs.

Main Methods:

• Assessed collagen I levels and ER-phagy receptor expression in activated HSCs.
• Utilized ATF6α-dependent processes and FAM134B deletion models.
• Investigated the impact of FAM134B on collagen I deposition and secretion.

Main Results:

• Collagen I levels are post-translationally regulated by autophagy, correlating with ER-phagy receptor expression.
• HSC activation induces ER-phagy flux and FAM134B expression, dependent on ATF6α.
• FAM134B deletion reduced intracellular collagen I and blocked TGFβ-induced collagen I deposition.

Conclusions:

• ER-phagy receptor FAM134B plays a pivotal role in collagen I deposition during liver fibrogenesis.
• FAM134B mediates collagen I degradation, impacting extracellular matrix accumulation in liver fibrosis.