Reticulophagy receptor FAM134C restrains BMP receptor signaling.

Area of Science:

• Cell Biology
• Molecular Biology
• Autophagy Research

Background:

• FAM134/RETREG proteins are known endoplasmic reticulum (ER)-phagy receptors crucial for cellular homeostasis.
• The non-ER-phagy functions of FAM134 proteins are largely unexplored.
• Understanding diverse roles of autophagy receptors is vital for cellular regulation.

Purpose of the Study:

• To investigate potential non-ER-phagy functions of FAM134 proteins.
• To determine if RETREG3/FAM134C interacts with and regulates other cellular components.
• To elucidate the role of FAM134C in BMP signaling pathways.

Main Methods:

• Investigated RETREG3/FAM134C as an autophagy receptor for the type I BMP receptor (BMPRIA/ALK3).
• Utilized chemical autophagy inhibition and knockdown of autophagy regulators (ATG5, Beclin-1).
• Disrupted the LC3-interacting region (LIR) motif in FAM134C and analyzed BMPR1A degradation in FAM134C-deficient mice.

Main Results:

• RETREG3/FAM134C selectively recruits BMPRIA into autophagosomes for degradation via autophagy.
• FAM134C-mediated BMPRIA degradation reduces BMP signaling strength.
• Autophagy inhibition or LIR motif disruption prevents BMPRIA degradation; FAM134C deficiency enhances BMP responses in mouse intestines.

Conclusions:

• FAM134C functions as a specific autophagy receptor for BMPRIA, controlling BMP signaling independently of ER-phagy.
• This novel mechanism highlights FAM134C's role in regulating cellular signaling pathways beyond ER turnover.
• FAM134C-mediated BMP signaling regulation impacts intestinal crypt regeneration.