Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

Yeping Wu; Ye-Wheen Lim; David A. Stroud; Nick Martel; Thomas E. Hall; Harriet P. Lo; Charles Ferguson; Michael T. Ryan; Kerrie-Ann McMahon; Robert G. Parton

doi:10.1016/j.devcel.2023.02.004

Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

Yeping Wu, Ye-Wheen Lim, David A. Stroud, Nick Martel, Thomas E. Hall, Harriet P. Lo, Charles Ferguson, Michael T. Ryan, Kerrie-Ann McMahon, Robert G. Parton

Research output: Contribution to journal › Article › Research › peer-review

25 Citations (Scopus)

Abstract

Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response.

Original language	English
Pages (from-to)	376-397.e1-4
Number of pages	27
Journal	Developmental Cell
Volume	58
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2023.02.004
Publication status	Published - 13 Mar 2023

Keywords

caveolae
CAVIN1
cell death
ferroptosis
lipid peroxidation
NRF2
oxidative stress

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10.1016/j.devcel.2023.02.004

Cite this

@article{034d2401786e4c1eb931dc1b96ff28ba,

title = "Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2",

abstract = "Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response.",

keywords = "caveolae, CAVIN1, cell death, ferroptosis, lipid peroxidation, NRF2, oxidative stress",

author = "Yeping Wu and Ye-Wheen Lim and Stroud, \{David A.\} and Nick Martel and Hall, \{Thomas E.\} and Lo, \{Harriet P.\} and Charles Ferguson and Ryan, \{Michael T.\} and Kerrie-Ann McMahon and Parton, \{Robert G.\}",

note = "Funding Information: This work was supported by the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.; grants APP1125390 and APP1140906 to M.T.R. and D.A.S. and fellowship APP1140851 to D.A.S.). R.G.P. is an Australian Research Council laureate fellow (FL210100107). The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at the University of Queensland. Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology with funding from the ACRF. We thank the Monash FlowCore and the Monash University Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. Conceptualization, Y.W. Y.-W.L. K.A.M. and R.G.P.; methodology, Y.W. Y.-W.L. and D.A.S.; formal analysis, Y.W. Y.-W.L. and D.A.S; writing – original draft, Y.W. Y.-W.L. D.A.S, K.A.M. and R.G.P.; writing – review \& editing, Y.W. K.A.M. R.G.P. Y.-W.L. H.P.L. T.E.H, M.T.R. and D.A.S.; supervision, Y.W. and R.G.P.; funding acquisition, R.G.P. M.T.R. and D.A.S. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.; grants APP1125390 and APP1140906 to M.T.R. and D.A.S. and fellowship APP1140851 to D.A.S.). R.G.P. is an Australian Research Council laureate fellow ( FL210100107 ). The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at the University of Queensland. Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology with funding from the ACRF . We thank the Monash FlowCore and the Monash University Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

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month = mar,

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doi = "10.1016/j.devcel.2023.02.004",

language = "English",

volume = "58",

pages = "376--397.e1--4",

journal = "Developmental Cell",

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publisher = "Cell Press",

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T1 - Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

AU - Wu, Yeping

AU - Lim, Ye-Wheen

AU - Stroud, David A.

AU - Martel, Nick

AU - Hall, Thomas E.

AU - Lo, Harriet P.

AU - Ferguson, Charles

AU - Ryan, Michael T.

AU - McMahon, Kerrie-Ann

AU - Parton, Robert G.

N1 - Funding Information: This work was supported by the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.; grants APP1125390 and APP1140906 to M.T.R. and D.A.S. and fellowship APP1140851 to D.A.S.). R.G.P. is an Australian Research Council laureate fellow (FL210100107). The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at the University of Queensland. Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology with funding from the ACRF. We thank the Monash FlowCore and the Monash University Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. Conceptualization, Y.W. Y.-W.L. K.A.M. and R.G.P.; methodology, Y.W. Y.-W.L. and D.A.S.; formal analysis, Y.W. Y.-W.L. and D.A.S; writing – original draft, Y.W. Y.-W.L. D.A.S, K.A.M. and R.G.P.; writing – review & editing, Y.W. K.A.M. R.G.P. Y.-W.L. H.P.L. T.E.H, M.T.R. and D.A.S.; supervision, Y.W. and R.G.P.; funding acquisition, R.G.P. M.T.R. and D.A.S. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: This work was supported by the National Health and Medical Research Council of Australia (grants APP1140064 and APP1150083 and fellowship APP1156489 to R.G.P.; grants APP1125390 and APP1140906 to M.T.R. and D.A.S. and fellowship APP1140851 to D.A.S.). R.G.P. is an Australian Research Council laureate fellow ( FL210100107 ). The authors acknowledge the use of the Microscopy Australia Research Facility at the Center for Microscopy and Microanalysis at the University of Queensland. Confocal microscopy was performed at the Australian Cancer Research Foundation (ACRF)/Institute for Molecular Bioscience (IMB) Dynamic Imaging Facility for Cancer Biology with funding from the ACRF . We thank the Monash FlowCore and the Monash University Biomedical Proteomics Facility for the provision of instrumentation, training, and technical support. Publisher Copyright: © 2023 Elsevier Inc.

PY - 2023/3/13

Y1 - 2023/3/13

N2 - Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response.

AB - Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole-cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to lipid-peroxidation-induced ferroptosis. Thus, caveolae, via lipid peroxidation and CAVIN1 release, maintain cellular susceptibility to oxidative-stress-induced cell death, demonstrating a crucial role for this organelle in cellular homeostasis and wound response.

KW - caveolae

KW - CAVIN1

KW - cell death

KW - ferroptosis

KW - lipid peroxidation

KW - NRF2

KW - oxidative stress

UR - https://www.scopus.com/pages/publications/85150311401

U2 - 10.1016/j.devcel.2023.02.004

DO - 10.1016/j.devcel.2023.02.004

M3 - Article

C2 - 36858041

AN - SCOPUS:85150311401

SN - 1534-5807

VL - 58

SP - 376-397.e1-4

JO - Developmental Cell

JF - Developmental Cell

IS - 5

ER -

Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

Abstract

Keywords

Access to Document

Other files and links

Translating membrane proteins into therapeutics; from bedside to bench

Systems approaches to understanding the assembly of mitochondrial machines

Systems approaches to understanding mitochondrial function and dysfunction in disease

FlowCore (FLOW)

Monash Proteomics & Metabolomics Platform (MPMP)

Cite this

Caveolae sense oxidative stress through membrane lipid peroxidation and cytosolic release of CAVIN1 to regulate NRF2

Abstract

Keywords

Access to Document

Other files and links

Projects

Translating membrane proteins into therapeutics; from bedside to bench

Systems approaches to understanding the assembly of mitochondrial machines

Systems approaches to understanding mitochondrial function and dysfunction in disease

Equipment

FlowCore (FLOW)

Monash Proteomics & Metabolomics Platform (MPMP)

Cite this