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Jonathan P. Bernardini

Canada's Michael Smith Genome Sciences Centre

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Grant Dewson

University of Melbourne

Peter E. Czabotar

University of Melbourne

Thibault Mayor

University of British Columbia

Ahmad Z. Wardak

Walter and Eliza Hall Institute of Medical Research

Iris K. L. Tan

Walter and Eliza Hall Institute of Medical Research

Guillaume Lessène

Walter and Eliza Hall Institute of Medical Research

Jason M. Brouwer

Walter and Eliza Hall Institute of Medical Research

Jarrod J. Sandow

University of Melbourne

Amanda E. Au

Walter and Eliza Hall Institute of Medical Research

Heather A. Baker

University of British Columbia

Cooperative Institutions

Walter and Eliza Hall Institute of Medical Research

University of Melbourne

Monash University

La Trobe University

University of British Columbia

Canada's Michael Smith Genome Sciences Centre

The Royal Melbourne Hospital

Australian Regenerative Medicine Institute

Peter MacCallum Cancer Centre

University of Sydney

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The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Heather A. Baker Jonathan P. Bernardini Veronika Csizmók Angel M. Madero Shriya Kamat

Abstract Mutations can result in the loss of a protein’s native function due to protein misfolding, which is generally handled by an intricate protein quality control network. To better understand the triaging mechanisms of misfolded cytosolic proteins, we screened a human mutation library to identify a panel of unstable mutations. The degradation of these mutated cytosolic proteins is largely dependent on the ubiquitin proteasome system. Using BioID proximity labelling, we found that the co-chaperones DNAJA1 and DNAJA2 are key interactors of one of the mutated proteins. Notably, the absence of DNAJA2 increases the turnover of the mutant protein but not of the wild-type protein. Our work indicates that missense mutations in cytosolic proteins can promote interactions with molecular chaperones that normally do not occur. Assessment of the broader panel of cytosolic mutant proteins shows that the co-chaperone DNAJA2 exhibits three distinct behaviours: acting to stabilize solely the mutant, both the wild-type and mutant proteins, or being dispensable. Our work illustrates how distinct elements of the protein homeostasis network are utilized in the presence of a cytosolic misfolded protein. Summary Statement We identified a panel of cytosolic mutant proteins degraded by the proteasome. DNAJA2 is often required to prevent mutant protein turnover, even if it is sometimes dispensable for the wild-type protein.

Chaperone (clinical)

Mutant protein

Endoplasmic-reticulum-associated protein degradation

Protein Degradation

Transport protein

10.1101/2024.02.15.580437

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BAK core dimers bind lipids and can be bridged by them

Nature Structural & Molecular Biology (2020)

Angus D. Cowan Nicholas A. Smith Jarrod J. Sandow Eugene A. Kapp Yepy H. Rustam

10.1038/s41594-020-0494-5

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Citations (58)

Dynamic reconfiguration of pro‐apoptotic BAK on membranes

The EMBO Journal (2021)

Jarrod J. Sandow Iris K. L. Tan Allan Shuai Huang Shashank Masaldan Jonathan P. Bernardini

Control reconfiguration

10.15252/embj.2020107237

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Citations (25)

Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

The EMBO Journal (2018)

Jonathan P. Bernardini Jason M. Brouwer Iris K. L. Tan Jarrod J. Sandow Shuai Huang

PINK1

10.15252/embj.201899916

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Citations (91)

Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2

The EMBO Journal (2020)

Theresa Klemm Gregor Ebert Dale J. Calleja Cody Allison Lachlan W. Richardson

ISG15

Deubiquitinating enzyme

Proteolysis

10.15252/embj.2020106275

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Citations (428)

The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations

Journal of Cell Science (2024)

Heather A. Baker Jonathan P. Bernardini Veronika Csizmók Angel M. Madero Shriya Kamat

Mutations can disrupt a protein's native function by causing misfolding, which is generally handled by an intricate protein quality control network. To better understand the triaging mechanisms of misfolded cytosolic proteins, we screened a human mutation library to identify a panel of unstable mutations. The degradation of these mutated cytosolic proteins is largely dependent on the ubiquitin proteasome system. Using BioID proximity labelling, we found that the co-chaperones DNAJA1 and DNAJA2 are key interactors with one of the mutated proteins. Notably, the absence of DNAJA2 increases the turnover of the mutant but not the wild-type protein. Our work indicates that specific missense mutations in cytosolic proteins can promote enhanced interactions with molecular chaperones. Assessment of the broader panel of cytosolic mutant proteins shows that the co-chaperone DNAJA2 exhibits two distinct behaviours: acting to stabilize a wide array of cytosolic proteins including wild type variants, and specifically “buffer” some mutant proteins to reduce their turnover. Our work illustrates how distinct elements of the protein homeostasis network are utilized in the presence of a cytosolic misfolded protein.

Chaperone (clinical)

Co-chaperone

Transport protein

10.1242/jcs.262019

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Citations (1)

The BH3-only proteins BIM and PUMA are not critical for the reticulocyte apoptosis caused by loss of the pro-survival protein BCL-XL

Cell Death and Disease (2017)

Alex R. D. Delbridge Brandon J. Aubrey Craig D. Hyland Jonathan P. Bernardini Ladina Di Rago

Abstract Anaemia is a major global health problem arising from diverse causes and for which improved therapeutic strategies are needed. Erythroid cells can undergo apoptotic cell death and loss of pro-survival BCL-XL is known to trigger apoptosis during late-stage erythroid development. However, the mechanism by which loss or pharmacological blockade of BCL-XL leads to erythroid cell apoptosis remains unclear. Here we sought to identify the precise stage of erythropoiesis that depends on BCL-XL. We also tested whether deficiency of BIM or PUMA, the two main pro-apoptotic antagonists of BCL-XL, could prevent reticulocyte death and anaemia caused by BCL-XL loss. Using an in vivo mouse model of tamoxifen-inducible Bclx gene deletion and in vitro assays with a BCL-XL-selective inhibitor, we interrogated each stage of erythrocyte differentiation for BCL-XL dependency. This revealed that reticulocytes, but not orthochromatic erythroblasts, require BCL-XL for their survival. Surprisingly, concurrent loss of BIM or PUMA had no significant impact on the development of anemia following acute BCL-XL deletion in vivo . However, analysis of mixed bone marrow chimaeric mice revealed that loss of PUMA, but not loss of BIM, partially alleviated impaired erythropoiesis caused by BCL-XL deficiency. Insight into how the network of pro-survival and pro-apoptotic proteins works will assist the development of strategies to mitigate the effects of abnormal cell death during erythropoiesis and prevent anaemia in patients treated with BCL-XL-specific BH3-mimetic drugs.

Puma

Bcl-xL

Reticulocyte

Ineffective erythropoiesis

10.1038/cddis.2017.304

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Citations (20)

Mutant TRP53 exerts a target gene-selective dominant-negative effect to drive tumor development

Genes & Development (2018)

Brandon J. Aubrey Ana Janic Yunshun Chen Catherine Chang Elizabeth Lieschke

Mutations in Trp53, prevalent in human cancer, are reported to drive tumorigenesis through dominant-negative effects (DNEs) over wild-type TRP53 function as well as neomorphic gain-of-function (GOF) activity. We show that five TRP53 mutants do not accelerate lymphomagenesis on a TRP53-deficient background but strongly synergize with c-MYC overexpression in a manner that distinguishes the hot spot Trp53 mutations. RNA sequencing revealed that the mutant TRP53 DNE does not globally repress wild-type TRP53 function but disproportionately impacts a subset of wild-type TRP53 target genes. Accordingly, TRP53 mutant proteins impair pathways for DNA repair, proliferation, and metabolism in premalignant cells. This reveals that, in our studies of lymphomagenesis, mutant TRP53 drives tumorigenesis primarily through the DNE, which modulates wild-type TRP53 function in a manner advantageous for neoplastic transformation.

Dominant negative

10.1101/gad.314286.118

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Citations (39)

Intrinsic apoptosis circumvents the functional decline of circulating platelets but does not cause the storage lesion

Irina Pleines Marion Lebois Pradnya Gangatirkar Amanda E. Au Rachael M. Lane

Life span

10.1182/blood-2017-11-816355

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Citations (23)

Regulation of the apoptotic machinery by the E3 ubiquitin ligase Parkin

Jonathan P. Bernardini

Ubiquitin-Protein Ligases

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Citations (0)