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Critical functions of FAM134 family members in endoplasmic reticulum remodeling, ER-phagy and collagen quality control

ABSTRACT: Degradation of the endoplasmic reticulum (ER) by selective autophagy (ER-phagy) is vital for cellular homeostasis. Here, we introduce FAM134A/RETREG2 and FAM134C/RETREG3 as new ER-phagy receptors. FAM134A and FAM134C exist in a relatively inactive state under basal conditions and require an activation signal to induce significant ER fragmentation. Molecular modeling and simulations implicate a single compact fold of FAM134A’s reticulon homology domain (RHD). In contrast, the RHDs of FAM134B and FAM134C are able to adopt at least three discrete conformations. These differences result in slower vesicle formation for FAM134A compared to FAM134C and mostly FAM134B. Global proteomic analyses of knockout MEFs indicate both distinct and overlapping roles for the Fam134s, with Fam134a being most distant from Fam134b and Fam134c. Fam134c appears to enhance and facilitate Fam134b’s role in maintaining pro-collagen-I levels and is therefore insufficient to compensate for its loss. By contrast, Fam134a has a particular mode of action in maintaining pro-collagen-I levels and is able to fully compensate loss of Fam134b or Fam134c upon over-expression in its wild-type or LIR mutant form.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: carmine cirillo

LAB HEAD: Paolo Grumati

PROVIDER: PXD025626 | Pride | 2021-06-23

REPOSITORIES: Pride

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