Rachael M. Lane

Monash University

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Co-Authors

Benjamin T. Kile

Monash University

Donald Metcalf

University of Melbourne

Katya J. Henley

Walter and Eliza Hall Institute of Medical Research

Emma C. Josefsson

University of Gothenburg

Marlyse A. Debrincat

Walter and Eliza Hall Institute of Medical Research

Stéphane Chappaz

Monash University

Marion Lebois

Walter and Eliza Hall Institute of Medical Research

M. J. D. White

University of the Witwatersrand

Sarah Ellis

Olivia Newton-John Cancer Wellness & Research Centre

Kate McArthur

Monash University

Cooperative Institutions

University of Melbourne

113

Walter and Eliza Hall Institute of Medical Research

103

Monash University

Australian Regenerative Medicine Institute

University of Cambridge

La Trobe University

The Royal Melbourne Hospital

Peter MacCallum Cancer Centre

University of Sydney

Baker Heart and Diabetes Institute

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Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production

Cell (2014)

M. J. D. White Kate McArthur Donald Metcalf Rachael M. Lane John C. Cambier

Sting

10.1016/j.cell.2014.11.036

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Citations (809)

Platelet Production Occurs Independently of Both the Intrinsic and Extrinsic Apoptosis Pathways

Blood (2012)

Emma C. Josefsson Deborah L. Burnett Marlyse A. Debrincat Katya J. Henley Rachael M. Lane

Thrombopoiesis

Intrinsic apoptosis

10.1182/blood.v120.21.389.389

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Citations (0)

Homeostatic apoptosis prevents competition-induced atrophy in follicular B cells

Cell Reports (2021)

Stéphane Chappaz Kate McArthur Liam Kealy Charity W. Law Maximilien Tailler

While the intrinsic apoptosis pathway is thought to play a central role in shaping the B cell lineage, its precise role in mature B cell homeostasis remains elusive. Using mice in which mature B cells are unable to undergo apoptotic cell death, we show that apoptosis constrains follicular B (FoB) cell lifespan but plays no role in marginal zone B (MZB) cell homeostasis. In these mice, FoB cells accumulate abnormally. This intensifies intercellular competition for BAFF, resulting in a contraction of the MZB cell compartment, and reducing the growth, trafficking, and fitness of FoB cells. Diminished BAFF signaling dampens the non-canonical NF-κB pathway, undermining FoB cell growth despite the concurrent triggering of a protective p53 response. Thus, MZB and FoB cells exhibit a differential requirement for the intrinsic apoptosis pathway. Homeostatic apoptosis constrains the size of the FoB cell compartment, thereby preventing competition-induced FoB cell atrophy.

Homeostasis

10.1016/j.celrep.2021.109430

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Citations (6)

Termination of STING responses is mediated via ESCRT‐dependent degradation

The EMBO Journal (2023)

Katherine R. Balka Rajan Venkatraman Tahnee L. Saunders Angus Shoppee Ee Shan Pang

Abstract cGAS‐STING signalling is induced by detection of foreign or mislocalised host double‐stranded (ds)DNA within the cytosol. STING acts as the major signalling hub, where it controls production of type I interferons and inflammatory cytokines. Basally, STING resides on the ER membrane. Following activation STING traffics to the Golgi to initiate downstream signalling and subsequently to endolysosomal compartments for degradation and termination of signalling. While STING is known to be degraded within lysosomes, the mechanisms controlling its delivery remain poorly defined. Here we utilised a proteomics‐based approach to assess phosphorylation changes in primary murine macrophages following STING activation. This identified numerous phosphorylation events in proteins involved in intracellular and vesicular transport. We utilised high‐temporal microscopy to track STING vesicular transport in live macrophages. We subsequently identified that the endosomal complexes required for transport (ESCRT) pathway detects ubiquitinated STING on vesicles, which facilitates the degradation of STING in murine macrophages. Disruption of ESCRT functionality greatly enhanced STING signalling and cytokine production, thus characterising a mechanism controlling effective termination of STING signalling.

Sting

ESCRT

Transport protein

10.15252/embj.2022112712

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Citations (37)

Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Journal of Clinical Investigation (2017)

Irina Pleines Joanne Woods Stéphane Chappaz Verity G. Kew Nicola Foad

Platelets are anuclear cells that are essential for blood clotting. They are produced by large polyploid precursor cells called megakaryocytes. Previous genome-wide association studies in nearly 70,000 individuals indicated that single nucleotide variants (SNVs) in the gene encoding the actin cytoskeletal regulator tropomyosin 4 (TPM4) exert an effect on the count and volume of platelets. Platelet number and volume are independent risk factors for heart attack and stroke. Here, we have identified 2 unrelated families in the BRIDGE Bleeding and Platelet Disorders (BPD) collection who carry a TPM4 variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia, a disorder characterized by low platelet count. N-Ethyl-N-nitrosourea–induced (ENU-induced) missense mutations in Tpm4 or targeted inactivation of the Tpm4 locus led to gene dosage–dependent macrothrombocytopenia in mice. All other blood cell counts in Tpm4-deficient mice were normal. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and had a mild effect on platelet function. Together, our findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder.

Platelet disorder

Mean platelet volume

Tropomyosin

10.1172/jci86154

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Citations (64)

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

The Journal of Experimental Medicine (2011)

Emma C. Josefsson Chloé James Katya J. Henley Marlyse A. Debrincat Kelly L. Rogers

It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets. Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors. To resolve this paradox, we generated mice with hematopoietic- or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax. We found that platelet production was unperturbed. In stark contrast, deletion of the prosurvival protein Bcl-x(L) resulted in megakaryocyte apoptosis and a failure of platelet shedding. This could be rescued by deletion of Bak and Bax. We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak(-/-) Bax(-/-) hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

Thrombopoiesis

Staurosporine

Megakaryocytopoiesis

10.1084/jem.20110750

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Citations (173)

Mutations in Tropomyosin 4 Cause Macrothrombocytopenia in Mice and Humans

Blood (2014)

Irina Pleines Joanne Woods Ernest Turro Nicola Foad Stéphane Chappaz

Mean platelet volume

10.1182/blood.v124.21.571.571

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Citations (1)

BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis

Science (2018)

Kate McArthur Lachlan Whitehead John M. Heddleston Lucy Li Benjamin Scott Padman

Mitochondrial apoptosis is mediated by BAK and BAX, two proteins that induce mitochondrial outer membrane permeabilization, leading to cytochrome c release and activation of apoptotic caspases. In the absence of active caspases, mitochondrial DNA (mtDNA) triggers the innate immune cGAS/STING pathway, causing dying cells to secrete type I interferon. How cGAS gains access to mtDNA remains unclear. We used live-cell lattice light-sheet microscopy to examine the mitochondrial network in mouse embryonic fibroblasts. We found that after BAK/BAX activation and cytochrome c loss, the mitochondrial network broke down and large BAK/BAX pores appeared in the outer membrane. These BAK/BAX macropores allowed the inner mitochondrial membrane to herniate into the cytosol, carrying with it mitochondrial matrix components, including the mitochondrial genome. Apoptotic caspases did not prevent herniation but dismantled the dying cell to suppress mtDNA-induced innate immune signaling.

Macropore

Efflux

10.1126/science.aao6047

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Citations (759)

Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets

The Journal of Cell Biology (2011)

Emma C. Josefsson Chloé James Katya J. Henley Marlyse A. Debrincat Kelly L. Rogers

It is believed that megakaryocytes undergo a specialized form of apoptosis to shed platelets.Conversely, a range of pathophysiological insults, including chemotherapy, are thought to cause thrombocytopenia by inducing the apoptotic death of megakaryocytes and their progenitors.To resolve this paradox, we generated mice with hematopoietic-or megakaryocyte-specific deletions of the essential mediators of apoptosis, Bak and Bax.We found that platelet production was unperturbed.In stark contrast, deletion of the prosurvival protein Bcl-x L resulted in megakaryocyte apoptosis and a failure of platelet shedding.This could be rescued by deletion of Bak and Bax.We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737.All three triggered mitochondrial damage, caspase activation, and cell death.Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737.In vivo, mice with a Bak / Bax / hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin.Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding.

10.1083/jcb1946oia12

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Citations (8)

A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis

Nature Chemical Biology (2019)

Mark F. van Delft Stéphane Chappaz Yelena Khakham Chinh T. Bui Marlyse A. Debrincat

Intrinsic apoptosis

UVB-induced apoptosis

10.1038/s41589-019-0365-8

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Citations (39)