TMEM259 (Membralin) is a multi-pass endoplasmic reticulum (ER) membrane protein that functions as a selective autophagy receptor in ER-associated protein quality control pathways 1. The protein assembles degradation complexes by recruiting MAN1B1 (α-mannosidase) through its luminal domains and VCP/p97 ATPase through its cytoplasmic regions, while containing a functional LC3-interacting region (LIR) motif in its cytoplasmic tail for autophagic delivery 2. TMEM259 demonstrates remarkable substrate specificity, primarily targeting viral class I fusion glycoproteins including SARS-CoV-2 spike, Ebola GP, influenza HA, and HIV-1 Env proteins through a ubiquitin-independent ER-to-lysosome-associated degradation (ERLAD) pathway, while misfolded host proteins are processed through conventional ERAD mechanisms 3. The protein plays critical roles in neuronal health, as astrocyte-specific deletion causes ALS-like motor defects by dysregulating glutamate homeostasis through reduced EAAT2 expression and TNF receptor activation 4. TMEM259 deficiency is associated with Alzheimer's disease pathogenesis, where reduced levels correlate with enhanced γ-secretase activity and increased β-amyloid pathology 5. Additionally, TMEM259 shows tumor-associated expression patterns in ovarian carcinomas, with tissue-specific splice variants 6.