Proteome of Fam134A/B/C knock-out MEFs

Selective degradation of endoplasmic reticulum (ER) via autophagy receptors is important to maintain cell homeostasis. In this study we identify FAM134A/RETREG2 and FAM134C/RETREG3 as bona fide ER-phagy receptors containing a classical and functional LIR motif. In contrast to the other family member FAM134B/RETREG1, over-expressed FAM134A and C are in a relatively inactive state, under basal conditions, and require an activation signal to fragment significant amounts of ER. Global proteomes analysis of knockout MEFs suggests distinct and overlapping functions of the three FAM134. Common functions are the maintenance of the ER shape and delivery of mis-folded pro-collagen I to lysosomes. Single knockout of Fam134a or Fam134c lead to swollen ER and massive intracellular accumulation of pro-collagen I. In this context, Fam134a but not Fam134c over-expression is able to recover collagen I levels, in Fam134b knockout MEFs, indicating distinct modes of action. Moreover, we provide evidence that Fam134a has a LIR-independent function in maintaining collagen I homeostasis in a co-receptor complex together with Fam134c. This pathway works in parallel to Fam134b, which in contrast is self-sufficient to drive ER-phagy.