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Metabolic regulation of KLHL proteins through O-glycosylation

Award Number: R01NS111588
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Metabolic regulation of KLHL proteins through O-glycosylation - Project Summary/Abstract The Kelch-like (KLHL) family of proteins are critical substrate adaptors for E3 ubiquitin ligases and mutations in KLHL genes underlie a range of human diseases, including cancer and neurodegeneration. However, the upstream regulation and downstream effects of most KLHL proteins remain poorly understood. The best-characterized KLHL protein is KEAP1, which binds to the CUL3/RBX1 E3 ligase components to mediate the ubiquitination and destruction of NRF2, a master transcriptional regulator of redox stress signaling. Redox-active compounds disable KEAP1, preventing the ubiquitination of NRF2 by KEAP1/CUL3/RBX1 and allowing NRF2 accumulation and activation. Recently, we demonstrated that KEAP1 is modified by O-GlcNAc, a nutrient-sensitive, reversible form of glycosylation, and this modification is required for efficient NRF2 ubiquitination and degradation. Blockade of KEAP1 O-GlcNAcylation by chemical inhibition or nutrient deprivation stabilizes and activates NRF2, revealing a new regulatory link between nutrient sensing and redox stress signaling. Interestingly, we recently discovered that the KLHL protein gigaxonin is also O-GlcNAcylated in a nutrient-dependent manner, indicating that glycosylation of KLHL proteins may be a general regulatory link between metabolic status and proteostasis. Based on these results, we hypothesize that nutrient-sensitive O-GlcNAcylation of KLHL proteins regulates proteostasis in response to a range of nutrient levels and metabolic stresses. To test this hypothesis, we will first exploit KEAP1 as a model KLHL protein to determine how various stresses impact KEAP1 glycosylation and activity. Next, we will determine how KEAP1 glycosylation affects the KEAP1/CUL3/RBX1 complex and KEAP1-substrate interactions, using both targeted biochemical and unbiased proteomic approaches. We will then determine the functional role of O-GlcNAcylation on gigaxonin, whose mutations cause the fatal human disease giant axon neuropathy (GAN). Finally, we will elucidate the relationship between gigaxonin glycosylation and GAN disease phenotypes using murine neuronal and human GAN patient fibroblast models. The successful completion of our project will provide broad and significant insights into KLHL protein regulation and function, and may point to new therapeutic opportunities in neurodegeneration, cancer and other diseases by manipulating KLHL proteins through O- GlcNAc modulation.


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: 2024 ( Subtotal = $0 )
2024	2022	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $526,958 )
2022	2022	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/24/2022	NON-COMPETING CONTINUATION	$526,958
														Subtotal = $526,958

Issue Date FY: 2021 ( Subtotal = $526,958 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2021	NON-COMPETING CONTINUATION	$526,958
														Subtotal = $526,958

Issue Date FY: 2020 ( Subtotal = $526,958 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/18/2020	NON-COMPETING CONTINUATION	$526,958
														Subtotal = $526,958

Issue Date FY: 2019 ( Subtotal = $541,390 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/6/2019	NEW	$541,390
														Subtotal = $541,390

Grand Total All Awards = $2,122,264

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Metabolic regulation of KLHL proteins through O-glycosylation

Award Number: R01NS111588

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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