Journal
EMBO REPORTS
Volume 22, Issue 9, Pages -Publisher
WILEY
DOI: 10.15252/embr.202052289
Keywords
autophagy; Collagen; ER stress; ER-phagy; FAM134
Categories
Funding
- Telethon Foundation [TMPGCBX16TT]
- Roche Foundation
- AFM-Telethon
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [259130777-SFB 1177]
- Else Kroener Fresenius Stiftung [2016_A196]
- EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant) [875510]
- Fondazione Umberto Veronesi
- Max Planck Society
- Projekt DEAL
- DFG [HU 800/6-2, RTG 1715]
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The degradation of the endoplasmic reticulum via selective autophagy is crucial for cellular homeostasis. FAM134A and FAM134C have been identified as ER-phagy receptors that can induce ER fragmentation and lysosomal degradation. The FAM134 paralogues play a significant role in maintaining ER morphology and increasing ER-phagy flux.
Degradation of the endoplasmic reticulum (ER) via selective autophagy (ER-phagy) is vital for cellular homeostasis. We identify FAM134A/RETREG2 and FAM134C/RETREG3 as ER-phagy receptors, which predominantly exist in an inactive state under basal conditions. Upon autophagy induction and ER stress signal, they can induce significant ER fragmentation and subsequent lysosomal degradation. FAM134A, FAM134B/RETREG1, and FAM134C are essential for maintaining ER morphology in a LC3-interacting region (LIR)-dependent manner. Overexpression of any FAM134 paralogue has the capacity to significantly augment the general ER-phagy flux upon starvation or ER-stress. Global proteomic analysis of FAM134 overexpressing and knockout cell lines reveals several protein clusters that are distinctly regulated by each of the FAM134 paralogues as well as a cluster of commonly regulated ER-resident proteins. Utilizing pro-Collagen I, as a shared ER-phagy substrate, we observe that FAM134A acts in a LIR-independent manner and compensates for the loss of FAM134B and FAM134C, respectively. FAM134C instead is unable to compensate for the loss of its paralogues. Taken together, our data show that FAM134 paralogues contribute to common and unique ER-phagy pathways.
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