Role of FAM134 paralogues in endoplasmic reticulum remodeling, ER-phagy, and Collagen quality control

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. Synopsis Selective degradation of the ER is essential to maintain ER homeostasis. This study characterizes FAM134A and FAM134C as ER-phagy receptors involved in Collagen quality control and identifies protein clusters differentially regulated by FAM134 paralogues. FAM134A and FAM134C are existent in an inhibited state under basal conditions and get activated upon stress/environmental changes. Dynamic of the RHD domain defines the ER fragmentation ability of FAM134 paralogues. FAM134 paralogues collectively drive Collagen I quality control, while managing additional, distinct substrate clusters. Graphical Abstract Selective degradation of the ER is essential to maintain ER homeostasis. This study characterizes FAM134A and FAM134C as ER-phagy receptors involved in Collagen quality control and identifies protein clusters differentially regulated by FAM134 paralogues.