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

Award Number: R35GM131681
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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The diverse roles of ER-Golgi trafficking machinery in autophagy and ER quality control - Project Summary Selective autophagy pathways use cargo receptors to degrade organelles, organelle subdomains, and misfolded proteins that fail to be degraded by the proteosome. Endoplasmic reticulum (ER) autophagy (also called ER-phagy) is a selective autophagy pathway that acts in ER quality control. ER-phagy cargo receptors connect an ER domain to the autophagosome biogenesis machinery via their ability to bind Atg8 family members (LC3 or GABARAP in mammals). The studies in this proposal are aimed at addressing two important unanswered questions in the field. First, we will ask how the conserved yeast ER-phagy cargo receptor, Atg40, fragments domains of the ER that it targets for degradation. Second, we will ask how Atg40 loads ER domains into autophagosomes, sealed double-membrane structures that are delivered to vacuoles (yeast) or lysosomes (mammals) for degradation. We have found that a non-canonical form of the yeast COPII coat subcomplex, Sec23-Lst1, works with Atg40 to package ER domains into autophagosomes during ER-phagy. The COPII coat is a multi-subunit coat complex that is known for its role in sorting ER proteins into transport carriers that traffic on the secretory pathway. We identified a novel role for Sec23-Lst1 in ER-phagy that is independent of its role in secretion. While the reticulon homology domain of Atg40 has been implicated in ER fission, it is unclear if Atg40 requires Sec23-Lst1 to fragment ER domains. An in vitro approach is needed to unambiguously answer this question. We have found that a variation of the COPII coat in vitro vesicle budding assay can be used to assess the requirements for Atg40-mediated ER fission. The COPII coat is formed by the sequential interactions of the Sar1 GTPase and cytoplasmic coat subcomplexes. We will use this in vitro assay to address if Atg40, Sec23- Lst1 and Atg8 are all needed for fission. Additionally, we will determine if purified Sar1, and other purified cytoplasmic COPII subcomplexes are also required. A long-term goal of these studies is to develop a similar in vitro ER fragmentation assay with mammalian COPII coat subcomplexes. To address how Atg40 sequesters membrane domains into autophagosomes, we will take advantage of an unusual phenotype we observed in lipid droplet (LD) deficient cells. Lipid droplets are ER-derived organelles that contain a neutral lipid core, triacylglycerides (TAG) and sterol esters (SE), surrounded by a phospholipid monolayer. When yeast cells are devoid of LD, resident ER membrane proteins fail to be delivered to the vacuole via ER-phagy. This defect appears to be due to the inability of the cargo receptor, Atg40, to sequester ER domains into autophagosomes. We will perform biochemical, genetic and localization studies to ask how LD are needed to couple Atg40 to its cargo. A long-term goal of these studies will be to address the role of LD in mammalian ER-phagy. These studies will be relevant to variety of metabolic disorders in humans, including diabetes and obesity.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $675,115 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	8	3/10/2026	NON-COMPETING CONTINUATION	$67,512
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	8	1/30/2026	NON-COMPETING CONTINUATION	$607,603
														Subtotal = $675,115

Issue Date FY: 2025 ( Subtotal = $675,115 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	004	7	8/15/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	003	7	8/5/2025	NON-COMPETING CONTINUATION	$67,512
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	002	7	1/21/2025	NON-COMPETING CONTINUATION	$607,603
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	11/25/2024	COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	12/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $675,115

Issue Date FY: 2024 ( Subtotal = $675,115 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	6	3/18/2024	COMPETING CONTINUATION	$675,115
														Subtotal = $675,115

Issue Date FY: 2023 ( Subtotal = $695,781 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	1/25/2023	SUPPLEMENT FOR EXPANSION	$20,666
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	3/3/2023	NON-COMPETING CONTINUATION	$675,115
														Subtotal = $695,781

Issue Date FY: 2022 ( Subtotal = $675,115 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	3/4/2022	NON-COMPETING CONTINUATION	$607,599
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	4	7/21/2022	NON-COMPETING CONTINUATION	$67,516
														Subtotal = $675,115

Issue Date FY: 2021 ( Subtotal = $715,217 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	3/11/2021	NON-COMPETING CONTINUATION	$674,581
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	3	9/17/2021	SUPPLEMENT FOR EXPANSION	$40,636
														Subtotal = $715,217

Issue Date FY: 2020 ( Subtotal = $679,847 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	7/15/2020	SUPPLEMENT FOR EXPANSION	$6,868
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	3/11/2020	NON-COMPETING CONTINUATION	$672,979
														Subtotal = $679,847

Issue Date FY: 2019 ( Subtotal = $665,826 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	1	7/17/2019	SUPPLEMENT FOR EXPANSION	$24,224
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	1	3/26/2019	NEW	$641,602
														Subtotal = $665,826

Grand Total All Awards = $5,457,131

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

Award Number: R35GM131681

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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