RETREG1 (reticulophagy regulator 1), also known as FAM134B, is a key endoplasmic reticulum (ER)-resident receptor that mediates reticulophagy, the selective autophagic degradation of ER subdomains. Primary function: RETREG1 contains a reticulon-homology domain and LC3-interacting regions (LIRs) that enable binding to autophagy modifiers LC3 and GABARAP, facilitating ER-phagy and removal of impaired ER fragments 1. Mechanism: USP20 deubiquitinates and stabilizes RETREG1 at specific ER subdomains, promoting reticulophagy under starvation conditions through recruitment of VAPs and autophagy proteins including WIPI2 2. RETREG1 oligomerization through its reticulon-homology domain is required for ER membrane scission; phosphorylation by CAMK2B enhances this activity under ER stress 3. Disease relevance: RETREG1 mutations cause hereditary sensory and autonomic neuropathy type 2B (HSAN2B); the FAM134B G216R variant exhibits gain-of-function defects with hyperactive oligomerization and excessive ER-phagy, leading to sensory neuron death 3. Clinical significance: During SARS-CoV-2 infection, ORF3A protein promotes RETREG1-mediated reticulophagy, inducing ER stress and inflammatory responses that facilitate viral infection 4. RETREG1 dysfunction impairs ER homeostasis and sensitizes cells to apoptosis 1.