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    Caspase-2 does not play a critical role in cell death induction and bacterial clearance during Salmonella infection
    Engel, S ; Doerflinger, M ; Lee, AR ; Strasser, A ; Herold, MJ ; Bedoui, S ; Bachem, A (Springer Nature, 2021-12)
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    Emerging connectivity of programmed cell death pathways and its physiological implications
    Bedoui, S ; Herold, MJ ; Strasser, A (Nature Research, 2020-11)
    The removal of functionally dispensable, infected or potentially neoplastic cells is driven by programmed cell death (PCD) pathways, highlighting their important roles in homeostasis, host defence against pathogens, cancer and a range of other pathologies. Several types of PCD pathways have been described, including apoptosis, necroptosis and pyroptosis; they employ distinct molecular and cellular processes and differ in their outcomes, such as the capacity to trigger inflammatory responses. Recent genetic and biochemical studies have revealed remarkable flexibility in the use of these PCD pathways and indicate a considerable degree of plasticity in their molecular regulation; for example, despite having a primary role in inducing pyroptosis, inflammatory caspases can also induce apoptosis, and conversely, apoptotic stimuli can trigger pyroptosis. Intriguingly, this flexibility is most pronounced in cellular responses to infection, while apoptosis is the dominant cell death process through which organisms prevent the development of cancer. In this Review, we summarize the mechanisms of the different types of PCD and describe the physiological and pathological processes that engage crosstalk between these pathways, focusing on infections and cancer. We discuss the intriguing notion that the different types of PCD could be seen as a single, coordinated cell death system, in which the individual pathways are highly interconnected and can flexibly compensate for one another.
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    Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice
    Brennan, MS ; Brinkmann, K ; Sola, GR ; Healey, G ; Gibson, L ; Gangoda, L ; Potts, MA ; Lieschke, E ; Wilcox, S ; Strasser, A ; Herold, MJ ; Janic, A (SPRINGERNATURE, 2024-02)
    Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of the diverse TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3, an RNA-binding zinc-finger protein involved in regulating alternative splicing, in haematopoietic cells by shRNA caused leukaemia only with the concomitant absence of the PUMA and p21, the critical effectors of TRP53-mediated apoptosis and cell cycle arrest respectively. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma-/-p21-/-Zmat3-/- triple knockout mice developed tumours at a significantly higher frequency compared to wild-type, Puma-/-Zmat3-/- or p21-/-Zmat3-/-deficient mice. Interestingly, we observed that the triple knockout and Puma-/-Zmat3-/- double deficient animals succumbed to lymphoma, while p21-/-Zmat3-/- animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Our findings reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, indicating that different TRP53 tumour suppressive pathways are more critical in different tissues.
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    BCL-W makes only minor contributions to MYC-driven lymphoma development
    Diepstraten, ST ; La Marca, JE ; Chang, C ; Young, S ; Strasser, A ; Kelly, GL (SPRINGERNATURE, 2023-09-08)
    The BH3-mimetic drug Venetoclax, a specific inhibitor of anti-apoptotic BCL-2, has had clinical success for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. Attention has now shifted towards related pro-survival BCL-2 family members, hypothesising that new BH3-mimetic drugs targeting these proteins may emulate the success of Venetoclax. BH3-mimetics targeting pro-survival MCL-1 or BCL-XL have entered clinical trials, but managing on-target toxicities is challenging. While increasing evidence suggests BFL-1/A1 is a resistance factor for diverse chemotherapeutic agents and BH3-mimetic drugs in haematological malignancies, few studies have explored the role of BCL-W in the development, expansion, and therapeutic responses of cancer. Previously, we found that BCL-W was not required for the ongoing survival and growth of various established human Burkitt lymphoma and diffuse large B cell lymphoma cell lines. However, questions remained about whether BCL-W impacts lymphoma development. Here, we show that BCL-W appears dispensable for MYC-driven lymphomagenesis, and such tumours arising in the absence of BCL-W show no compensatory changes to BCL-2 family member expression, nor altered sensitivity to BH3-mimetic drugs. These results demonstrate that BCL-W does not play a major role in the development of MYC-driven lymphoma or the responses of these tumours to anti-cancer agents.
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    The BCL-2 family member BID plays a role during embryonic development in addition to its BH3-only protein function by acting in parallel to BAX, BAK and BOK
    Ke, FS ; Holloway, S ; Uren, RT ; Wong, AW ; Little, MH ; Kluck, RM ; Voss, AK ; Strasser, A (WILEY, 2022-08-01)
    The intrinsic apoptosis pathway, regulated by the BCL-2 protein family, is essential for embryonic development. Using mice lacking all known apoptosis effectors, BAX, BAK and BOK, we have previously defined the processes during development that require apoptosis. Rare Bok-/- Bax-/- Bak-/- triple knockout (TKO) mice developed to adulthood and several tissues that were thought to require apoptosis during development appeared normal. This raises the question if all apoptosis had been abolished in the TKO mice or if other BCL-2 family members could act as effectors of apoptosis. Here, we investigated the role of BID, generally considered to link the extrinsic and intrinsic apoptosis pathways, acting as a BH3-only protein initiating apoptosis upstream of BAX and BAK. We found that Bok-/- Bax-/- Bak-/- Bid-/- quadruple knockout (QKO) mice have additional developmental anomalies compared to TKO mice, consistent with a role of BID, not only upstream but also in parallel to BAX, BAK and BOK. Mitochondrial experiments identified a small cytochrome c-releasing activity of full-length BID. Collectively, these findings suggest a new effector role for BID in the intrinsic apoptosis pathway.
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    PD-1 cooperates with AIRE-mediated tolerance to prevent lethal autoimmune disease
    Policheni, AN ; Teh, CE ; Robbins, A ; Tuzlak, S ; Strasser, A ; Gray, DHD (NATL ACAD SCIENCES, 2022-04-12)
    Immunological tolerance is established and maintained by a diverse array of safeguards that work together to protect against autoimmunity. Despite the identification of numerous tolerogenic processes, the basis for cooperation among them remains poorly understood. We sought to identify synergy among several well-defined tolerance mediators that alone provide protection only from mild autoimmune symptoms in C57BL/6 mice: BIM, AIRE, CBL-B, and PD-1. Survey of a range of compound mutant mice revealed that the combined loss of the autoimmune regulator, AIRE, with PD-1 unleashed a spontaneous, lethal autoimmune disease. Pdcd1−/−Aire−/− mice succumbed to cachexia before adulthood, with near-complete destruction of the exocrine pancreas. Such fatal autoimmunity was not observed in Pdcd1−/−Bim−/−, Bim−/−Aire−/−, or Cblb−/−Bim−/− mice, suggesting that the cooperation between AIRE-mediated and PD-1–mediated tolerance was particularly potent. Immune profiling revealed largely normal development of FOXP3+ regulatory T (Treg) cells in Pdcd1−/−Aire−/− mice, yet excessive, early activation of effector T cells. Adoptive transfer experiments demonstrated that autoimmune exocrine pancreatitis was driven by conventional CD4+ T cells and could not be prevented by the cotransfer of Treg cells from wild-type mice. The development of autoimmunity in mixed bone marrow chimeras supported these observations, indicating that failure of recessive tolerance was responsible for disease. These findings reveal a potent tolerogenic axis between AIRE and PD-1 that has implications for our understanding of how immune checkpoint blockade might synergize with subclinical defects in central tolerance to elicit autoimmune disease.
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    Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis
    Potts, MA ; Mizutani, S ; Garnham, AL ; Suen, CSNLW ; Kueh, AJ ; Tai, L ; Pal, M ; Strasser, A ; Herold, MJ (SPRINGERNATURE, 2023-06)
    Many lymphoid malignancies arise from deregulated c-MYC expression in cooperation with additional genetic lesions. While many of these cooperative genetic lesions have been discovered and their functions characterised, DNA sequence data of primary patient samples suggest that many more do exist. However, the nature of their contributions to c-MYC driven lymphomagenesis have not yet been investigated. We identified TFAP4 as a potent suppressor of c-MYC driven lymphoma development in a previous genome-wide CRISPR knockout screen in primary cells in vivo [1]. CRISPR deletion of TFAP4 in Eµ-MYC transgenic haematopoietic stem and progenitor cells (HSPCs) and transplantation of these manipulated HSPCs into lethally irradiated animals significantly accelerated c-MYC-driven lymphoma development. Interestingly, TFAP4 deficient Eµ-MYC lymphomas all arose at the pre-B cell stage of B cell development. This observation prompted us to characterise the transcriptional profile of pre-B cells from pre-leukaemic mice transplanted with Eµ-MYC/Cas9 HSPCs that had been transduced with sgRNAs targeting TFAP4. This analysis revealed that TFAP4 deletion reduced expression of several master regulators of B cell differentiation, such as Spi1, SpiB and Pax5, which are direct target genes of both TFAP4 and MYC. We therefore conclude that loss of TFAP4 leads to a block in differentiation during early B cell development, thereby accelerating c-MYC-driven lymphoma development.
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    Loss of TRP53 reduces but does not overcome dependency of lymphoma cells on MCL-1
    Aubrey, BJ ; Brennan, MS ; Diepstraten, ST ; Wang, Z ; Chang, C ; Herold, MJ ; Strasser, A ; Kelly, GL (SPRINGERNATURE, 2022-05)
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    Functional flexibility and plasticity in immune control of systemic Salmonella infection
    Engel, S ; Bachem, A ; Strugnell, RA ; Strasser, A ; Herold, MJ ; Bedoui, S (CURRENT BIOLOGY LTD, 2023-08)
    Immunity to systemic Salmonella infection depends on multiple effector mechanisms. Lymphocyte-derived interferon gamma (IFN-γ) enhances cell-intrinsic bactericidal capabilities to antagonize the hijacking of phagocytes as replicative niches for Salmonella. Programmed cell death (PCD) provides another means through which phagocytes fight against intracellular Salmonella. We describe remarkable levels of flexibility with which the host coordinates and adapts these responses. This involves interchangeable cellular sources of IFN-γ regulated by innate and adaptive cues, and the rewiring of PCD pathways in previously unknown ways. We discuss that such plasticity is likely the consequence of host-pathogen coevolution and raise the possibility of further functional overlap between these seemingly distinct processes.
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    Deletion of Gpatch2 does not alter Tnf expression in mice
    Dalseno, D ; Anderton, H ; Kueh, A ; Herold, MJ ; Silke, J ; Strasser, A ; Bouillet, P (SPRINGERNATURE, 2023-03-27)
    The cytokine TNF has essential roles in immune defence against diverse pathogens and, when its expression is deregulated, it can drive severe inflammatory disease. The control of TNF levels is therefore critical for normal functioning of the immune system and health. We have identified GPATCH2 as a putative repressor of Tnf expression acting post-transcriptionally through the TNF 3' UTR in a CRISPR screen for novel regulators of TNF. GPATCH2 is a proposed cancer-testis antigen with roles reported in proliferation in cell lines. However, its role in vivo has not been established. We have generated Gpatch2-/- mice on a C57BL/6 background to assess the potential of GPATCH2 as a regulator of Tnf expression. Here we provide the first insights into Gpatch2-/- animals and show that loss of GPATCH2 affects neither basal Tnf expression in mice, nor Tnf expression in intraperitoneal LPS and subcutaneous SMAC-mimetic injection models of inflammation. We detected GPATCH2 protein in mouse testis and at lower levels in several other tissues, however, the morphology of the testis and these other tissues appears normal in Gpatch2-/- animals. Gpatch2-/- mice are viable, appear grossly normal, and we did not detect notable aberrations in lymphoid tissues or blood cell composition. Collectively, our results suggest no discernible role of GPATCH2 in Tnf expression, and the absence of an overt phenotype in Gpatch2-/- mice warrants further investigation of the role of GPATCH2.