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Novel role of endoplasmic reticulum-associated degradation in iron metabolism

Award Number: R01DK128077
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Novel role of endoplasmic reticulum-associated degradation in iron metabolism - My laboratory is interested in the (patho-)physiological importance of endoplasmic reticulum (ER)-associated degradation (ERAD), a principal ER quality-control machinery to clear misfolded ER proteins for cytosolic proteasomal degradation. The Sel1L-Hrd1 protein complex represents the most evolutionarily conserved ERAD machinery from yeast to humans. In the past several years, we and others have reported the physiological significance of Sel1L-Hrd1 ERAD in health and disease in a cell-type and substrate-specific manner; however, our understanding of its physiological role remains limited. In the preliminary data of this application, we performed an unbiased proteomics screen that led to the identification of ceruloplasmin (Cp) protein, a ferroxidase regulating iron homeostasis, as an ERAD substrate in the liver. We further showed that both wildtype and a disease mutant Cp are misfolding-prone and are ubiquitinated and degraded by Sel1L- Hrd1 ERAD. Moreover, hepatocyte-specific Sel1L-deficient mice exhibit elevated Cp activity in the circulation and are resistant to iron deficiency-induced hypochromic microcytic anemia. These data point to a critical role of hepatocyte Sel1L-Hrd1 ERAD in Cp biogenesis and systemic iron homeostasis. These findings are exciting because Cp is an essential regulator in iron homeostasis and because Cp missense mutations in humans cause a clinical condition known as aceruloplasminemia, characterized by abnormal iron accumulation in organs. However, the biogenesis of nascent Cp in the ER remains unexplored. Hence, the overarching hypothesis of this application is that Sel1L-Hrd1 ERAD in hepatocytes controls systemic iron homeostasis by regulating the turnover of both wildtype and disease mutant Cp proteins under physiological and pathological conditions, respectively. We will accomplish the following three Aims: (1) Determine the physiological and pathological significance of Sel1L-Hrd1 ERAD in iron metabolism; (2) Delineate the molecular mechanism underlying Cp biogenesis regulated by ERAD; and (3) Delineate the pathological importance of ERAD in the pathogenesis of aceruloplasminemia. Completion of these studies will not only delineate the significance and molecular mechanism underlying ERAD-mediated regulation of iron metabolism, but also provide novel insights into how iron metabolism is regulated under basal and pathological conditions. Relevance to human health: Disorders of iron homeostasis affect millions of individuals worldwide, which cause anemia in deficiency and increase the risk of diabetes, liver and kidney diseases upon overload. This application, with parallel physiological and biochemical studies, will establish a direct link between ERAD and iron metabolism, uncover novel mechanisms underlying ERAD and misfolding-associated proteotoxic stress, and advance our understanding of disease pathogenesis associated with protein folding defects in general.


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 = $363,375 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	11/26/2024	NON-COMPETING CONTINUATION	$363,375
														Subtotal = $363,375

Issue Date FY: 2024 ( Subtotal = $387,600 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	005	3	7/24/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$397,352
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	12/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$363,375
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/7/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$24,225
2024	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/6/2023	NON-COMPETING CONTINUATION	$0
2024	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	2	7/24/2024	NON-COMPETING CONTINUATION	-$385,000
2024	2022	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	1	7/24/2024	NEW	-$12,352
														Subtotal = $387,600

Issue Date FY: 2023 ( Subtotal = $385,000 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/9/2023	NON-COMPETING CONTINUATION	$38,500
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	11/28/2022	NON-COMPETING CONTINUATION	$346,500
														Subtotal = $385,000

Issue Date FY: 2022 ( Subtotal = $385,000 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/29/2021	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $1,520,975

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Novel role of endoplasmic reticulum-associated degradation in iron metabolism

Award Number: R01DK128077

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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