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.\cite{Kurth2009} 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