# The diverse roles of ER-Golgi trafficking machinery in autophagy and ER quality control

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $675,115

## Abstract

Project Summary
 The studies in this proposal are aimed at understanding the role of secretory machinery on two different
types of autophagy pathways that use autophagosomes, bulk autophagy and the selective autophagy of the
endoplasmic reticulum (ER). Defects in autophagy have been linked to cancer and a variety of human
diseases, including neurodegenerative diseases. Autophagy is a conserved catabolic process that targets
cellular components for degradation. When autophagy is induced, membranes coalesce to engulf components
targeted for degradation. Once these membranes seal to form an autophagosome their contents are delivered
to the lysosome or vacuole for degradation. My laboratory has shown the importance of the Rab GTPase Ypt1
(Rab1 in mammals) in initiating these events.
 When cells are starved for nutrients, bulk autophagy is upregulated to rapidly make more nutrients. The
high demand for membrane to make more autophagosomes during starvation leads to a dramatic
reorganization of intracellular membranes. We have shown that the secretory pathway is downregulated during
starvation and membranes from the secretory pathway are redirected to the bulk autophagy pathway.
Furthermore, we found that phosphorylation of secretory machinery plays a key role in reprogramming
membranes for bulk autophagy. A future goal of our studies is to identify the kinases that trigger the conserved
membrane rearrangement events that take place during starvation in yeast (Saccharomyces cerevisiae) and
mammalian cells. We will also address the requirements for fusing autophagosomal membranes with
membranes from the early secretory pathway.
 Selective autophagy pathways use cargo receptors to degrade toxic aggregates and damaged
organelle subdomains. These receptors link cargo, that is targeted for degradation, to the autophagy
machinery. Our studies on autophagy have now expanded to include the selective degradation of the ER, also
called ER-phagy. Understanding ER-phagy is of therapeutic importance as this pathway appears to be
essential for the clearance of toxic aggregates from the ER. How ER-phagy targets damaged domains of the
ER for degradation and severs these domains from the rest of the network remains unknown. We initiated a
genetic screen in yeast and have identified key conserved factors that act in ER-phagy. Some of these factors
are components of the early secretory pathway that also work in conjunction with Atg40. Atg40 is a conserved
cargo receptor that has been implicated in the packaging of ER subdomains into autophagosomes. A goal of
our studies is to understand how Atg40 works with these newly identified conserved components to target and
sever ER subdomains during ER-phagy in both yeast and mammalian cells.

## Key facts

- **NIH application ID:** 10370408
- **Project number:** 5R35GM131681-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Susan FERRO-NOVICK
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $675,115
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370408

## Citation

> US National Institutes of Health, RePORTER application 10370408, The diverse roles of ER-Golgi trafficking machinery in autophagy and ER quality control (5R35GM131681-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370408. Licensed CC0.

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