SUMMARYSurface receptor and transporter protein down-regulation drives cell signaling, quality control and metabolism underlying diverse physiology. After endocytosis, proteins are delivered to endosomes where ESCRTs package them into intralumenal vesicles, which are degraded by 5 acid hydrolases upon fusion with lysosomes. However, reports of ESCRT-independent surface protein degradation are emerging suggesting that alternative, non-canonical pathways exist.Using Saccharomyces cerevisiae as a model, here we show that in response to substrates, protein misfolding or TOR signaling, some internalized surface transporters (Hxt3, Itr1, Aqr1) bypass ESCRTs en route to the lysosome membrane where they are sorted into an area that is 10 internalized as an intralumenal fragment (ILF) and degraded upon organelle fusion. This ILF pathway also degrades typical ESCRT client proteins (Mup1, Can1, Ste3) when ESCRT function is impaired. As the underlying machinery is conserved, we speculate that the ILF pathway is an important contributor to receptor and transporter down-regulation in all eukaryotes. 15 HIGHLIGHTS and eTOC BLURB• The ILF pathway degrades surface polytopic proteins that bypass ESCRTs 20• Surface proteins are degraded by the ILF pathway in response to misfolding, TOR or substrates• The ILF pathway compensates for ESCRT impairment• The ILF pathway is important for receptor and transporter down-regulation 25It is not clear how surface receptor and transporter down-regulation occurs independent of ESCRT function. Here, McNally and Brett show that internalized surface polytopic proteins that bypass ESCRTs are delivered to lysosome membranes where they are sorted and packaged for degradation by the intralumenal fragment (ILF) pathway upon homotypic organelle fusion.peer-reviewed)

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