Biology subjects

Bouchier-Hayes, L.

Publications and source records attributed to Bouchier-Hayes, L..

3 recordsLinked to original sources

bioRxiv2023

Caspase-2 is essential for proliferation and self-renewal of nucleophosmin-mutated acute myeloid leukemia.

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm, and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ AML but not in NPM1wt cells. Strikingly, in NPM1c+ cells, loss of caspase-2 results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells with and without caspase-2. Together, these results show that caspase-2 is essential for proliferation and self-renewal of AML cells that have mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function and may even be a druggable target to treat NPM1c+ AML and prevent relapse.

cancer biology↗

bioRxiv2021

Caspase-2 regulates S-phase cell cycle events to protect from DNA damage accumulation independent of apoptosis

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1- and early S-phase. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, S-phase-associated chromosomal aberrations, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 reduces replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division or DNA damage-induced cell cycle arrest. Thus, our data supports a model where caspase-2 regulates cell cycle events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

cell biology↗

bioRxiv2020

Non-redundant roles of caspase-4 and caspase-5 in heme driven- IL-1β release and cell death

Excessive release of heme from red blood cells is a key pathophysiological feature of several disease states including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and endothelium. Here, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1{beta}. Heme-induced IL-1{beta} release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4, and caspase-5 are essential for heme-induced IL-1{beta} release, while caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme acts as a damage associated molecular pattern (DAMP) that can engage canonical and non-canonical inflammasome activation as a key mediator of inflammation in macrophages. FootnotesFunding for the project includes NIH/NIDDK T32DK060445 (BEB, BAR), NIH/NIDDK F32DK121479 (BEB), NIH/NIGMS R01GM121389 (LBH), NIH/NHLBI R01HL114567 (JDB, GMV), NIH/NHLBI R01-HL136415 (JMF), and CPRIT-RP180672, NIHCA125123 and NIHRR024574 (Cytometry and Cell Sorting Core at Baylor College of Medicine) Key PointsO_LIHeme induces oligomerization of caspase-1, caspase-4, and caspase-5. C_LIO_LIHeme-induced IL-1{beta} release requires both caspase-4 and caspase-5. C_LIO_LICaspase-4 alone contributes to heme-induced cell death. C_LI

immunology↗