White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.

Yeung, SH-S; Lee, RH-S; Cheng, GW-Y; Ma, IW-T; Kofler, J; Kent, C; Ma, F; Herrup, K; Fornage, M; Arai, K; Tse, K-H

White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.

Yeung, SH-S Lee, RH-S Cheng, GW-Y Ma, IW-T Kofler, J Kent, C Ma, F Herrup, K Fornage, M Arai, K Tse, K-H

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Publisher:: WILEY
Publication Type:: Journal Article
Citation:: FASEB J, 2024, 38, (19), pp. e70059
Issue Date:: 2024-10-15

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Field	Value	Language
dc.contributor.author	Yeung, SH-S
dc.contributor.author	Lee, RH-S
dc.contributor.author	Cheng, GW-Y
dc.contributor.author	Ma, IW-T
dc.contributor.author	Kofler, J
dc.contributor.author	Kent, C
dc.contributor.author	Ma, F
dc.contributor.author	Herrup, K
dc.contributor.author	Fornage, M
dc.contributor.author	Arai, K
dc.contributor.author	Tse, K-H
dc.date.accessioned	2025-01-29T00:27:17Z
dc.date.available	2024-09-05
dc.date.available	2025-01-29T00:27:17Z
dc.date.issued	2024-10-15
dc.identifier.citation	FASEB J, 2024, 38, (19), pp. e70059
dc.identifier.issn	0892-6638
dc.identifier.issn	1530-6860
dc.identifier.uri	http://hdl.handle.net/10453/184560
dc.description.abstract	White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. Genome-wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.
dc.format	Print
dc.language	eng
dc.publisher	WILEY
dc.relation.ispartof	FASEB J
dc.relation.isbasedon	10.1096/fj.202400689RR
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 0606 Physiology, 1116 Medical Physiology
dc.subject.classification	Biochemistry & Molecular Biology
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3208 Medical physiology
dc.subject.mesh	Animals
dc.subject.mesh	Autophagy
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Brain
dc.subject.mesh	White Matter
dc.subject.mesh	Risk Factors
dc.subject.mesh	Male
dc.subject.mesh	Autophagy-Related Protein-1 Homolog
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Brain
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Animals
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Risk Factors
dc.subject.mesh	Autophagy
dc.subject.mesh	Male
dc.subject.mesh	White Matter
dc.subject.mesh	Autophagy-Related Protein-1 Homolog
dc.subject.mesh	Animals
dc.subject.mesh	Autophagy
dc.subject.mesh	Mice
dc.subject.mesh	Humans
dc.subject.mesh	Endothelial Cells
dc.subject.mesh	Brain
dc.subject.mesh	White Matter
dc.subject.mesh	Risk Factors
dc.subject.mesh	Male
dc.subject.mesh	Autophagy-Related Protein-1 Homolog
dc.subject.mesh	Microtubule-Associated Proteins
dc.subject.mesh	Mice, Inbred C57BL
dc.subject.mesh	Ubiquitin-Protein Ligases
dc.title	White matter hyperintensity genetic risk factor TRIM47 regulates autophagy in brain endothelial cells.
dc.type	Journal Article
utslib.citation.volume	38
utslib.location.activity	United States
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	0606 Physiology
utslib.for	1116 Medical Physiology
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access	*
dc.rights.license	This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated	2025-01-29T00:27:12Z
pubs.issue	19
pubs.publication-status	Published
pubs.volume	38
utslib.citation.issue	19

Abstract:

White matter hyperintensity (WMH) is strongly correlated with age-related dementia and hypertension, but its pathogenesis remains obscure. Genome-wide association studies identified TRIM47 at the 17q25 locus as a top genetic risk factor for WMH formation. TRIM family is a class of E3 ubiquitin ligase with pivotal functions in autophagy, which is critical for brain endothelial cell (ECs) remodeling during hypertension. We hypothesize that TRIM47 regulates autophagy and its loss-of-function disturbs cerebrovasculature. Based on transcriptomics and immunohistochemistry, TRIM47 is found highly expressed by brain ECs in human and mouse, and its transcription is upregulated by artificially induced autophagy while downregulated in hypertension-like conditions. Using in silico simulation, immunocytochemistry and super-resolution microscopy, we predicted a highly conserved binding site between TRIM47 and the LIR (LC3-interacting region) motif of LC3B. Importantly, pharmacological autophagy induction increased Trim47 expression on mouse ECs (b.End3) culture, while silencing Trim47 significantly increased autophagy with ULK1 phosphorylation induction, transcription, and vacuole formation. Together, we demonstrate that TRIM47 is an endogenous inhibitor of autophagy in brain ECs, and such TRIM47-mediated regulation connects genetic and physiological risk factors for WMH formation but warrants further investigation.

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http://hdl.handle.net/10453/184560