Functional characterization of a novel endosome and Golgi associated degradation (EGAD) system


CALL: 2019

DOMAIN: BM - Life Sciences, Biology and Medicine





HOST INSTITUTION: Innsbruck Medical University

KEYWORDS: membrane protein degradation,Endosome and Golgi Associated Degradation (EGAD),Proteasome,membrane proteostasis,membrane extraction

START: 2019-10-01

END: 2022-09-30


Submitted Abstract

Ubiquitin-dependent protein degradation pathways are essential to maintain the integrity of the eukaryotic proteome. Endoplasmic reticulum (ER) associated degradation (ERAD) selectively ubiquitinates and extracts transmembrane proteins from the ER and targets them for proteasomal degradation. Ubiquitinated membrane proteins from post-ER compartments (plasma membrane, Golgi, lysosomes and endosomes) are typically sorted by the endosomal sorting complexes required for transported (ESCRT) along the MVB pathway into lysosomes for degradation.The Teis Lab has identified an additional membrane protein degradation pathway in Saccharomyces cerevisiae. At the Golgi and on endosomes, the membrane embedded Dsc ubiquitin ligase complex targets the membrane protein Orm2, a negative regulator of sphingolipid synthesis, for degradation in a proteasome-dependent manner in response to TORC2-Ypk1 signaling. So far, the Dsc complex has only been described to initiate the degradation of a few transmembrane proteins from post-ER compartments in an ESCRT- and lysosome-dependent manner. How the Dsc complex can discriminate between lysosomal or proteasomal substrates is so far unknown. The overall aim of my project will be to define how the Dsc complex is embedded in cellular proteostasis. Therefore, I plan to use the following three approaches:(i)I aim to identify additional substrates of the Dsc complex to understand which biochemical properties set apart proteasomal- from lysosomal-Dsc substrates.(ii)I plan to dissect the molecular mechanism for extracting ubiquitinated membrane proteins from endosomes and Golgi.(iii)I will use forward genetics (Saturated Transposon Analysis in Yeast (SATAY)) to understand systematically how the Dsc is embedded in cellular proteostasis networks. The results of my PhD thesis will help to understand how orphaned transmembrane proteins are detected in post-ER compartments and specifically targeted for proteasomal- or lysosomal-dependent degradation to restore cellular proteostasis.

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