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Autophagosome closure by the ESCRT machinery

Award Number: R01GM127954
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: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Autophagosome closure by the ESCRT machinery - Project Summary/Abstract The goal of this project is to address a fundamental gap in knowledge on how phagophores are closed to form double membrane autophagosomes. During macroautophagy (hereafter autophagy), crescent-shaped phagophores elongate around cytoplasmic material and seal to generate double-membrane autophagosomes that fuse with lysosomes for cargo degradation. As the phagophore rim narrows, the membranes must undergo fission to separate the inner and outer membranes in a process that bears resemblance to endosomal sorting complexes required for transport (ESCRT)-mediated membrane scission. Using our elegant HaloTag-LC3 autophagosome completion assay, we provided the first experimental evidence for the ESCRT machinery in mammalian phagophore closure and identified the ESCRT-I subunit VPS37A as critical factor for the recruitment of downstream ESCRTs to the phagophore. Notably, we found that the N-terminal putative ubiquitin E2 variant (PUEV) domain of VPS37A is uniquely required for autophagosome closure but is dispensable for other ESCRT-mediated membrane abscission processes, including endosome receptor sorting and cytokinesis. Compartment-specific targeting factors initiate the sequential recruitment of the four ESCRT complexes (ESCRT-I, -II, -III and VPS4) to the membrane scission site. While the phagophore-specific targeting factors for the VPS37A-containing ESCRT-I complex are unknown, our preliminary study has revealed that VPS37A PUEV interacts with highly curved membranes containing anionic lipids and lipid packing defects, which are all features of the phagophore rim. We hypothesize that the PUEV selectively interacts with highly curved phagophore membranes to target ESCRT-I to the phagophore. Furthermore, our preliminary work has revealed that ESCRT recruitment to phagophores requires protein ubiquitylation and the LC3/GABARAP conjugation machinery, leading us to believe that the stabilization of membrane-associated ESCRT-I requires additional interactions with phagophore-associated ubiquitylated cargo. We are in an ideal position to test our hypotheses in the following Specific Aims: (1) to determine how VPS37A targets ESCRT-I to phagophores and directs the assembly of downstream ESCRTs during autophagosome biogenesis; (2) to identify phagophore-specific targeting factors for ESCRT-I during autophagy. As autophagy is involved in numerous physiological and pathological processes, these studies will have far-reaching implications for human health and disease.


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: 2025 ( Subtotal = $347,987 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	8	8/1/2025	NON-COMPETING CONTINUATION	$347,987
														Subtotal = $347,987

Issue Date FY: 2024 ( Subtotal = $348,013 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	003	7	8/1/2024	NON-COMPETING CONTINUATION	$348,013
2024	2022	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	002	5	7/23/2024	COMPETING CONTINUATION	$94,113
2024	2021	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	4	7/23/2024	NON-COMPETING CONTINUATION	-$75,886
2024	2021	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	4	7/23/2024	SUPPLEMENT FOR EXPANSION	-$18,227
														Subtotal = $348,013

Issue Date FY: 2023 ( Subtotal = $348,038 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	6	9/7/2023	NON-COMPETING CONTINUATION	$348,038
														Subtotal = $348,038

Issue Date FY: 2022 ( Subtotal = $348,062 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	002	5	9/12/2022	COMPETING CONTINUATION	$340,512
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	003	5	9/20/2022	COMPETING CONTINUATION	$7,550
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	4	9/2/2022	NON-COMPETING CONTINUATION	$0
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	4	9/2/2022	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $348,062

Issue Date FY: 2021 ( Subtotal = $387,246 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	4	3/10/2021	NON-COMPETING CONTINUATION	$312,246
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	001	4	9/10/2021	SUPPLEMENT FOR EXPANSION	$75,000
														Subtotal = $387,246

Issue Date FY: 2020 ( Subtotal = $312,315 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	3	3/24/2020	NON-COMPETING CONTINUATION	$312,315
														Subtotal = $312,315

Issue Date FY: 2019 ( Subtotal = $312,381 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	2	3/4/2019	NON-COMPETING CONTINUATION	$312,381
														Subtotal = $312,381

Issue Date FY: 2018 ( Subtotal = $312,445 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY DR C1607	HERSHEY	PA	17033	DAUPHIN	USA	Biomedical Research and Research Training	000	1	6/21/2018	NEW	$312,445
														Subtotal = $312,445

Grand Total All Awards = $2,716,487

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Autophagosome closure by the ESCRT machinery

Award Number: R01GM127954

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: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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