Abstract
Surface receptor and transporter protein down-regulation is assumed to be exclusively mediated by the canonical multivesicular body (MVB) pathway and ESCRTs (Endosomal Sorting Complexes Required for Transport). However, few surface proteins are known to require ESCRTs for down-regulation, and reports of ESCRT-independent degradation are emerging, suggesting that alternative pathways exist. Here, using Saccharomyces cerevisiae as a model, we show that the hexose transporter Hxt3 does not require ESCRTs for down-regulation conferring resistance to 2-deoxyglucose. This is consistent with GFP-tagged Hxt3 bypassing ESCRT-mediated entry into intralumenal vesicles at endosomes. Instead, Hxt3-GFP accumulates on vacuolar lysosome membranes and is sorted into an area that, upon fusion, is internalized as an intralumenal fragment (ILF) and degraded. Moreover, heat stress or cycloheximide trigger degradation of Hxt3-GFP and other surface transporter proteins (Itr1, Aqr1) by this ESCRT-independent process. How this ILF pathway compares to the MVB pathway and potentially contributes to physiology is discussed.
Highlights
Surface receptor and transporter protein down-regulation is assumed to be exclusively mediated by the canonical multivesicular body (MVB) pathway and ESCRTs (Endosomal Sorting Complexes Required for Transport)
Here we demonstrate that whereas some internalized surface polytopic proteins (Can1) rely on the canonical ESCRTdependent MVB pathway for downregulation, other presumed ESCRT-client proteins (Hxt[3], Itr[1], Aqr1) bypass ESCRT function at endosomes and, upon MVB-vacuole fusion, are delivered to vacuole membranes where they are selectively sorted for degradation by the intralumenal fragment (ILF) pathway
The assumption that all surface proteins are degraded by the MVB pathway is no longer reasonable, and we speculate that the ILF pathway may play an important role in surface polytopic protein downregulation
Summary
Surface receptor and transporter protein down-regulation is assumed to be exclusively mediated by the canonical multivesicular body (MVB) pathway and ESCRTs (Endosomal Sorting Complexes Required for Transport). Surface proteins are labeled with ubiquitin— in response to changing substrate levels, heat stress to induce protein misfolding or cellular signaling for example—and selectively internalized by the process of endocytosis[13,15,16,17,18,19,20] Within the cell, they are sent to endosomes where they encounter ESCRTs (endosomal sorting complexes required for transport). We recently discovered that vacuolar polytopic proteins, e.g., ion and nutrient transporters, are selectively sorted into the boundary membrane for degradation in response to substrate levels, misfolding by heat stress or TOR (Target Of Rapamycin) signaling triggered by cycloheximide[37]. The possibility exists that surface polytopic proteins may be degraded by the ILF pathway if they can be delivered to the vacuole membrane after internalization
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