MOSPD3 mediates the ER recruitment of ATG2A to promote autophagy

ATG2A transfers glycerophospholipids from the endoplasmic reticulum (ER) to the expanding phagophore during autophagy, but how it is anchored to the ER in mammalian cells has been unclear. Here, we identify MOSPD3, an atypical member of the VAP family, as the ER adaptor for ATG2A. Endogenous MOSPD3 occupies ER subdomains adjacent to nascent autophagic structures, and it captures ATG2A through a direct interaction between its major sperm protein (MSP) domain and an FFNT (two phenylalanines in a neutral tract) motif near the ATG2A N terminus. Disrupting either side of this interface abolishes ER recruitment and prevents ATG2A from supporting autophagy. Its paralog MOSPD1 acts redundantly on ATG2B, and cells lacking both adaptors are defective in autophagic flux. MSP-FFNT recognition therefore provides the ER-side anchor that positions the ATG2A lipid-transfer bridge for autophagosome biogenesis.