Formation of the autolysosome involves SNARE-mediated autophagosome-lysosome fusion, which is mediated by a combination of the Qa SNARE STX17 (syntaxin 17), the Qbc SNARE SNAP29 and the R-SNAREs VAMP7/8. 2 very recent reports have now implicated another R-SNARE with a longin domain, YKT6, in this fusion process. Interestingly, these reports painted two different pictures of YKT6's involvement. Studies in HeLa cells indicated that YKT6, acting independently of STX17, could form a separate SNARE complex with SNAP29 and another Qa SNARE to mediate autophagosome-lysosome fusion. Conversely, work in Drosophila larvae fat cells showed that while Ykt6 could form a SNARE complex with Snap29 and Syx17/Stx17, it is readily outcompeted by lysosomal Vamp7 in this regard. Moreover, its activity in autophagosome-lysosome fusion is not impaired by mutation of the supposedly critical ionic zero-layer residue from R to Q. In this regard, YKT6 may therefore act in a noncanonical way to regulate fusion. Here, we ponder on the fresh mechanistic perspectives on the final membrane fusion step of macroautophagy/autophagy offered by these new findings. Further, we propose another possible mechanism as to how YKT6 might act, which may provide some reconciliation to the differences observed. Abbreviations: LD: longin domain.
Keywords: Autophagosome; SNARE; Syntaxin 17 (STX17); YKT6; autophagy; lysosome.