ERphagy driven phenotypes and implications on human health:
While the list of ERphagy related receptors and signaling proteins is sure to grow, the few recently described players have been implicated in human health and disease. Prior to uncovering this pathway, it was found that mutations in FAM134b causes severe sensory and autonomic neuropathy in humans.25 These FAM134b mutants cause cis-golgi alterations and induce an increased rate of apoptosis in primary dorsal root ganglion neurons. A loss of these specific neurons could explain the early loss of nociception seen in individuals with this genetic disorder, although this has not yet been explored. Further, in mice, FAM134b null strains show reduced number of sensory axon numbers in peripheral neurons, suggesting a conserved role for this protein across mammalian species. The cell type specific phenotypes seen in vivo suggest that FAM134b may be a cell type specific ER receptor.
Indeed, a second ERphagy receptor, CCPG1 has been shown to have cell type specific phenotypes as well. CCPG1 deficiency causes degeneration of pancreatic acinar cells in mice while all other tissues remain relatively unaffected. MIST1, a tissue-specific transcription factor expressed in professional secretory cells, binds to the promoter region of CCPG1 and may be responsible for this pancreatic secretory cell phenotype.26 Moving forward, it will be critical to identify other tissue specific transcription factors that bind to promoters of ERphagy receptors. As ER homeostasis is crucial in the vast majority of cell types, it is likely that there are both ERphagy receptors and related transcriptional regulators yet to be identified in mammals.
On the pathogenic front, the ER is utilized by flaviviruses during host infection and replication. Accordingly, there are ER related proteins that serve as restriction factors to inhibit viral replication as first line of defense. FAM134b has been identified as a host cell restriction factor for both dengue virus and zika virus drastically deepening the implication on ERphagy regulation on human health27. Depletion of FAM134b enhances the replication of both dengue and zika virus and presumably, humans with genetic mutations in this gene would be more susceptible to this virus. Zika virus has seen major expansion in recent years to new and naive populations driving serious developmental defects including microcephaly.28,29 The saliency of this public health issue may serve to drive a more rapid investigation of the ERphagy pathway and could result in valuable therapeutics.
This connection between and ERphagy receptor and viral replication poses several questions: Do other ERphagy receptors have a similar effect on viral replication? Is ERphagy necessary in regulating viral infection? And if so, what other proteins yet to be identified to could be at play?
Future Directions and Concluding Remarks:
Mechanistically, ERphagy presents a unique challenge to the general understanding of selective autophagy due of the ER’s large size and continuous nature. In order to be internalized into autophagophore the membrane must first separate from the rest of the ER. This raises several questions about the signals involved in ERphagy as well as the order of events. Does the ER membrane bud off before interacting with autophagy receptors? How do the receptors regulating this process distinguish ER that is to be recycled from the rest of the organelle? What machinery is involved in spatiotemporally regulating these budding events? All of these basic questions are not yet well understood but are certainly interesting and relevant to basic cellular biology.
The rapid influx of literature in this field over the past 4 years has only scraped the surface on the mechanisms and signaling involved in selective autophagy of the ER. While exciting and quickly progressing, more questions have been posed about ERphagy than have been answered. As the field matures, it will be crucial to define golden standards for quantifying ERphagy. This development of phenotypic assays will open up the world of functional screening and lend to more rapid uncovering of this signaling pathway. As genome-wide screening and unbiased omics scale approaches will surely provide new insight to ER autophagy mechanisms, the full scope of these biomolecular interactions remains untouched at current.