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NINJ1 mediates inflammatory cell death, PANoptosis, and drives lethality during heat stress

ABSTRACT: NINJ1 mediates inflammatory cell death, PANoptosis, and drives lethality during heat stress

PROVIDER: PRJNA1061511 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27441423.fastq.gz	Fastqsanger.gz
	SRR27441424.fastq.gz	Fastqsanger.gz
	SRR27441425.fastq.gz	Fastqsanger.gz
	SRR27441426.fastq.gz	Fastqsanger.gz

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NINJ1 mediates inflammatory cell death, PANoptosis, and drives lethality during heat stress

Project description:Innate immunity provides the first line of defense through key mechanisms, including pyrogen and cytokine production and cell death. While elevated body temperature during infection is beneficial, heat stress (HS) can lead to inflammation and pathology. Links between HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during HS remain unclear. Here, we use diverse genetic approaches to elucidate innate immune pathways in HS. Our results show that bacteria and LPS robustly increase inflammatory cell death, PANoptosis, during HS. NINJ1 is the key executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioners. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients experiencing HS.

2024-01-05 | GSE252609 | GEO

Mus musculus

Project description:NINJ1 mediates inflammatory cell death, PANoptosis, and drives lethality during heat stress

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NINJ1 mediates inflammatory cell death, PANoptosis, and lethality during infection conditions and heat stress.

Project description:Innate immunity provides the first line of defense through multiple mechanisms, including pyrogen production and cell death. While elevated body temperature during infection is beneficial to clear pathogens, heat stress (HS) can lead to inflammation and pathology. Links between pathogen exposure, HS, cytokine release, and inflammation have been observed, but fundamental innate immune mechanisms driving pathology during pathogen exposure and HS remain unclear. Here, we use multiple genetic approaches to elucidate innate immune pathways in infection or LPS and HS models. Our results show that bacteria and LPS robustly increase inflammatory cell death during HS that is dependent on caspase-1, caspase-11, caspase-8, and RIPK3 through the PANoptosis pathway. Caspase-7 also contributes to PANoptosis in this context. Furthermore, NINJ1 is an important executioner of this cell death to release inflammatory molecules, independent of other pore-forming executioner proteins, gasdermin D, gasdermin E, and MLKL. In an in vivo HS model, mortality is reduced by deleting NINJ1 and fully rescued by deleting key PANoptosis molecules. Our findings suggest that therapeutic strategies blocking NINJ1 or its upstream regulators to prevent PANoptosis may reduce the release of inflammatory mediators and benefit patients.

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Transferrin Receptor contributes to PANoptosis in thyroid cancer

Project description:PANoptosis is a novel type of cell death triggered by the cross-talk of three types of cell death (necrosis, apoptosis, and pyroptosis). Nevertheless, the molecular mechanisms associated with PANoptosis in thyroid cancer (TC) remain uncharted. Therefore, this study explored the effect of TFRC on PANoptosis in TC cells in vitro.

2025-08-31 | GSE280138 | GEO

PANoptosis, a combination of inflammatory cell death mechanisms, induced by Ophiobolin A in breast cancer cell lines

Project description:An unmet challenge in managing breast cancer is treatment failure due to resistance to apoptosis-inducing chemotherapies. Thus, it is important to identify novel non-apoptotic therapeutic agents. Several non-apoptotic programmed cell death pathways utilize specific cellular signaling events to trigger lytic and pro-inflammatory cell death. PANoptosis, which encompasses pyroptosis, apoptosis and necroptosis, is of paramount importance in the regulation of cell death and immune responses. Our study illustrates that ophiobolin A (OpA) is an anti-cancer agent that triggers lytic cell death in breast cancer cells, including triple-negative breast cancer (TNBC), via a mechanism dependent on RIPK1. This study reveals that OpA induces typical pyroptosis-like characteristics, including cellular swelling, plasma membrane rupture, GSDMD cleavage and release of cytokines in breast cancer cells. The involvement of caspase 3, RIPK1, and GSDMD suggests that PANoptosis is activated upon OpA treatment in breast cancer. The induction of pro-inflammatory cell death suggests potential applications for OpA in cancer treatment.

2024-09-17 | GSE277026 | GEO

ADAR1 restricts ZBP1–mediated immune response and PANoptosis to promote tumorigenesis

Project description:Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wildtype mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1–dependent manner. Our findings suggest that ADAR1 suppresses ZBP1–mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to inform therapeutic strategies for cancer and other diseases.

2021-10-19 | GSE184323 | GEO

NINJ1 induces plasma membrane rupture and DAMP release during ferroptosis

Project description:Ferroptosis is a regulated form of necrotic cell death caused by an iron-dependent accumulation of oxidized phospholipids in cellular membranes, which culminates in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death executors. Yet, whether ferroptosis-associated PMR is actively executed by a protein or driven by osmotic pressure remains unknown. Here, we investigated the role of ninjurin-1 (NINJ1), the recently identified executor of pyroptosis-associated PMR, in ferroptosis. We report that during ferroptosis NINJ1 oligomerizes and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the early steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx and cell swelling. By contrast, NINJ1 is required for early loss of plasma membrane integrity, an event that precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular patterns (DAMPs) from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.

2024-02-15 | PXD047622 | Pride

19-11-D Gene expression levels in Ninj1 KO BMDMs

Project description:We have identified mouse Ninj1 as a protein responsible for plasma membrane integrity following cell death stimuli. Ninj1 KO BMDMs have a distinct bubble morphology wherein cell cytoplasmic contents fail to be released following cell death. To determine contributing factors to Ninj1 KO morphology, we performed RNAseq in WT and Ninj1 KO murine BMDMs with or without priming.

2020-12-18 | GSE156395 | GEO

PANoptosis, a combination of inflammatory cell death mechanisms, induced by Ophiobolin A in breast cancer cell lines

Project description:PANoptosis, a combination of inflammatory cell death mechanisms, induced by Ophiobolin A in breast cancer cell lines

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Nucleoptosis: Nucleolar ISG20L2 mediates cell death through genomic DNA degradation

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