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The Discovery of Molecules and Mechanisms of the Rhomboid Superfamily

Award Number: R35GM133565
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: 08/15/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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The Discovery of Molecules and Mechanisms of the Rhomboid Superfamily - Project Summary/Abstract Elimination of misfolded proteins by ER-associated protein degradation (ERAD) ensures that proteins entering the secretory pathway are correctly folded and that ER stress is maintained at acceptably low levels. All ERAD pathways include a protein translocation process termed retrotranslocation, in which ubiquitinated ERAD substrates are selectively extracted from the ER before degradation by the cytosolic 26S proteasome. Despite its commonality in ERAD, many features of retrotranslocation have remained mysterious. We have made a major breakthrough in understanding retrotranslocation. By employing whole-genome yeast arrays, we have discovered the rhomboid family protein Dfm1 to be critical for the removal of membrane substrates and has opened the door to a deep mechanistic understanding of retrotranslocation and rhomboid protein biology. Notably, we identified two additional biological functions of derlin Dfm1 where 1) it employs a chaperone-like role for alleviating aggregated misfolded membrane protein stress and 2) regulates sphingolipid metabolism. Overall, this places Dfm1 at the heart of vast membrane-related processes. To gain deeper biological insights from these new findings, we will: 1) Define the mechanism associated with Dfm1-mediated retrotranslocation. 2) Explore a new stress-state associated with aggregated misfolded membrane proteins. 3) Determine how Dfm1 regulates sphingolipid metabolism. We will use a multifaceted approach including biochemistry, cell biology, genetics, structural biology, proteomics, and advanced microscopy to address these central questions in rhomboid proteins and membrane biology. We will leverage our unique in vivo and in vitro assays-and continue to devise new ones-to dissect the basic mechanisms of rhomboid-mediated retrotranslocation and its place in cell and organismal biology. A mechanistic understanding of rhomboid protein biology in protein quality control, stress alleviation, and lipid metabolism will establish foundational biological insights while unveiling therapeutic targets for a variety of critical pathways including protein misfolding, protein quality control, ER stress, and lipid dysregulation.


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 = $472,015 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	6	1/28/2025	COMPETING CONTINUATION	$472,015
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	5	1/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $472,015

Issue Date FY: 2023 ( Subtotal = $388,440 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	5	6/27/2023	NON-COMPETING CONTINUATION	$378,590
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	5/23/2023	SUPPLEMENT FOR EXPANSION	$9,850
														Subtotal = $388,440

Issue Date FY: 2022 ( Subtotal = $378,590 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	4	6/28/2022	NON-COMPETING CONTINUATION	$378,590
														Subtotal = $378,590

Issue Date FY: 2021 ( Subtotal = $378,590 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	3	6/30/2021	NON-COMPETING CONTINUATION	$378,590
														Subtotal = $378,590

Issue Date FY: 2020 ( Subtotal = $438,968 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	000	2	7/1/2020	NON-COMPETING CONTINUATION	$377,445
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Biomedical Research and Research Training	001	2	8/13/2020	SUPPLEMENT FOR EXPANSION	$61,523
														Subtotal = $438,968

Issue Date FY: 2019 ( Subtotal = $377,445 )
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	8/13/2019	NEW	$377,445
														Subtotal = $377,445

Grand Total All Awards = $2,434,048

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The Discovery of Molecules and Mechanisms of the Rhomboid Superfamily

Award Number: R35GM133565

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: 08/15/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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