ESCRTs function directly on the lysosome membrane to downregulate ubiquitinated lysosomal membrane proteins

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Abstract

The lysosome plays an important role in maintaining cellular nutrient homeostasis. Regulation of nutrient storage can occur by the ubiquitination of certain transporters that are then sorted into the lysosome lumen for degradation. To better understand the underlying mechanism of this process, we performed genetic screens to identify components of the sorting machinery required for vacuole membrane protein degradation. These screens uncovered genes that encode a ubiquitin ligase complex, components of the PtdIns 3-kinase complex, and the ESCRT machinery. We developed a novel ubiquitination system, Rapamycin Induced Degradation (RapiDeg), to test the sorting defects caused by these mutants. These tests revealed that ubiquitinated vacuole membrane proteins recruit ESCRTs to the vacuole surface, where they mediate cargo sorting and direct cargo delivery into the vacuole lumen. Our findings demonstrate that the ESCRTs can function at both the late endosome and the vacuole membrane to mediate cargo sorting and intra-luminal vesicle formation.

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Lu Zhu

Weill Institute of Cell and Molecular Biology, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Jeff Ryan Jorgensen

Weill Institute of Cell and Molecular Biology, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Ming Li

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Ya-Shan Chuang

Weill Institute of Cell and Molecular Biology, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Scott D Emr

Weill Institute of Cell and Molecular Biology, Cornell University, Ithaca, United States

For correspondence
sde26@cornell.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5408-6781

Funding

Cornell University (Scott Emr research grant CU3704)

Scott D Emr

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.