ERphagy in mammalian systems:
One of the major distinctions between selective and non-selective autophagy is the inclusion of receptor proteins in the signaling pathway. In contrast to non-selective autophagy which is driven primarily in response to serum starvation, functions such as the removal of damaged organelles, elimination of pathogens and the unfolded protein response (UPR), require a more tightly regulated and directed process. Autophagy receptors serve to direct different types of selective autophagy by bridging the cargo to core autophagy machinery. Specifically, these receptors characteristically have an LC3 interacting motif domain (LIR) domains that allows for ATG8 protein binding in addition to other motifs that drive localization of the receptor.\cite{Ichimura2008} ATG8 proteins of the LC3 and GABARAP family proteins are autophagy ubiquitin-like modifiers that are crucial for autophagosome biogenesis and directing selective autophagy.\cite{Rozenknop2011} To this end, four primary autophagic receptors for ERphagy have be identified in mammalian cells: FAM134b, RTN3, SEC62 and CCDG.\cite{Khaminets2015,Grumati2017,Fumagalli2016,Smith2018} While each of these receptors have a LIR domain for canonical ATG8 bridging, there are stark differences between the function and structure of these proteins.
FAM134b and RTN3 are the human homologues of atg39 and atg40 proteins that were first discovered in yeast.21 While both of these proteins contain four reticulon homology domains and at least one LIR motif, they perform non-redundant roles in the turnover of specific ER subdomains.\cite{Mochida2015} FAM134b localizes to ER sheets, while RTN3 localizes to ER tubules.\cite{Grumati2017} Each receptor will subsequently mediate an interaction between autophagosomes and allow for turnover of distinct portions of the ER. Further, RTN3 contains an additional layer of regulation in degradation of the ER, in that only the long isoform of RTN3 is able to mediate the ER-autophagosome interaction. Short isoforms of this protein lack the 6 LIR domains required for this function. Grumati et al. 2017 show that clustering of RTN3L protein can fulfill requirements for ERphagy, while hetero-oligomerization of the long and short isoforms actually cause stabilization of the tubules. This postulates a major question: Under which cellular stimulations/ conditions would you expect to a change in equilibrium between the seven RTN3 splice isoforms.