Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia

Li, Xiaoming; Li, Fang; Zhang, Xixi; Zhang, Haiwei; Zhao, Qun; Li, Ming; Wu, Xiaoxia; Wang, Lingxia; Liu, Jianling; Ou, Yangjing; Xing, Mingyan; Zhang, Yue; Deng, Jiangshan; Wang, Xiuzhe; Luo, Yan; Li, Jinbao; Zhao, Yang

doi:10.1038/s41418-022-00938-9

Cited by 25 publications

(18 citation statements)

References 74 publications

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“…RTECs will undergo multiple modalities of cell death during AKI. To determine the cell death pathway that was most affected by loss-of-DUSP2, we firstly extensively analyzed the executioners of apoptosis ( Caspase3 ), necroptosis ( Mlkl and Ripr3 ), ferroptosis ( Gpx4 and Slc7a11 ), and pyroptosis ( Casp1 and Gsdmd ) in RTECs 31 - 35 . Interestingly, comparing to IRI/ Dusp2 fl/fl mice, we found that only the executioner of pyroptosis ( Gsdmd ) was significantly upregulated in RTECs of IRI/ Dusp2 CKO mice (Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Xiong¹,

Ran²,

Yingguo³

et al. 2022

Theranostics

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Rationale: Acute kidney injury (AKI) is pathologically characterized by renal tubular epithelial cell (RTEC) death and interstitial inflammation, while their pathogenesis remains incompletely understood. Dual-specificity phosphatase 2 (DUSP2) recently emerges as a crucial regulator of cell death and inflammation in a wide range of diseases, but its roles in renal pathophysiology are largely unknown. Methods: The expression of DUSP2 in the kidney was characterized by histological analysis in renal tissues from patients and mice with AKI. The role and mechanism of DUSP2-mediated inhibition of tubular epithelial cell pyroptosis in AKI were evaluated both in vivo and in vitro , and confirmed in RTEC-specific deletion of DUSP2 mice. Results: Here, we show that DUSP2 is enriched in RTECs in the renal tissue of both human and mouse and mainly positions in the nucleus. Further, we reveal that loss-of-DUSP2 in RTECs not only is a common feature of human and murine AKI but also positively contributes to AKI pathogenesis. Especially, RTEC-specific deletion of DUSP2 sensitizes mice to AKI by promoting RTEC pyroptosis and the resultant interstitial inflammation. Mechanistic studies show that gasdermin D (GSDMD), which mediates RTEC pyroptosis, is identified as a transcriptional target of activated STAT1 during AKI, whereas DUSP2 as a nuclear phosphatase deactivates STAT1 to restrict GSDMD-mediated RTEC pyroptosis. Importantly, DUSP2 overexpression in RTECs via adeno-associated virus-mediated gene transfer significantly ameliorates AKI. Conclusion: Our findings demonstrate a hitherto unrecognized role of DUSP2-STAT1 axis in regulating RTEC pyroptosis in AKI, highlighting that DUSP2-STAT1 axis is an attractive therapeutic target for AKI.

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Section: Resultsmentioning

confidence: 99%

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Xiong¹,

Ran²,

Yingguo³

et al. 2022

Theranostics

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“…and mitogen-activated protein kinase (MAPK) signaling pathways, inhibiting caspase-8 activation and promoting cell survival (72, [78][79][80]. If TNF-a recruits TRADD, FADD, procaspase-8, and RIPK1 to form complex iia, then complex iia promotes activation of caspase-8, and activated caspase-8 undergoes apoptosis by activating caspase-3 (73,81,82). When caspase-8 is inhibited or its activity level is relatively low, RIPK1 recruits RIPK3 and both recruit MLKL through the RIP homotypic interaction motif (RHIM) to form complex iib, also known as necrosome (83,84).…”

Section: Regulatory Mechanisms Of Necroptosismentioning

confidence: 99%

“…After TNF-α interacts with TNFR, TNFR1 starts to recruit the downstream protein molecules TNFR1- associated death domain protein (TRADD), RIPK1, TRAF2/5, and linear ubiquitin chain assembly complex (LU⁃BAC) proteins to form complex I, in which RIPK1 is polyubiquitinated and activates nuclear RIPK1 polyubiquitinates and activates the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, inhibiting caspase-8 activation and promoting cell survival ( 72 , 78 – 80 ). If TNF-α recruits TRADD, FADD, pro–caspase-8, and RIPK1 to form complex iia, then complex iia promotes activation of caspase-8, and activated caspase-8 undergoes apoptosis by activating caspase-3 ( 73 , 81 , 82 ). When caspase-8 is inhibited or its activity level is relatively low, RIPK1 recruits RIPK3 and both recruit MLKL through the RIP homotypic interaction motif (RHIM) to form complex iib, also known as necrosome ( 83 , 84 ).…”

Section: Necroptosismentioning

confidence: 99%

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Zhang

Liu

2022

Front. Immunol.

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Ovarian cancer (OC) is one of the most common malignancies that causes death in women and is a heterogeneous disease with complex molecular and genetic changes. Because of the relatively high recurrence rate of OC, it is crucial to understand the associated mechanisms of drug resistance and to discover potential target for rational targeted therapy. Cell death is a genetically determined process. Active and orderly cell death is prevalent during the development of living organisms and plays a critical role in regulating life homeostasis. Ferroptosis, a novel type of cell death discovered in recent years, is distinct from apoptosis and necrosis and is mainly caused by the imbalance between the production and degradation of intracellular lipid reactive oxygen species triggered by increased iron content. Necroptosis is a regulated non-cysteine protease–dependent programmed cell necrosis, morphologically exhibiting the same features as necrosis and occurring via a unique mechanism of programmed cell death different from the apoptotic signaling pathway. Pyroptosis is a form of programmed cell death that is characterized by the formation of membrane pores and subsequent cell lysis as well as release of pro-inflammatory cell contents mediated by the abscisin family. Studies have shown that ferroptosis, necroptosis, and pyroptosis are involved in the development and progression of a variety of diseases, including tumors. In this review, we summarized the recent advances in ferroptosis, necroptosis, and pyroptosis in the occurrence, development, and therapeutic potential of OC.

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“…Presently, apoptosis is recognized as an immunologically silent cell death as this kind of cell elimination exhibits little risk to the host and occurs without activating inflammatory molecules . Conversely, cell death via necroptosis releases DAMPs, further inducing inflammation and organic detriment. − …”

Section: Introductionmentioning

confidence: 99%

“…9 In the alternate scenario, caspase 8 cleaves RIPK1 and activates caspase 3, thereby inducing apoptosis. 10 After MLKL is phosphorylated by RIPK3 and forms oligomers as the executor of necroptosis, oligomeric MLKLs translocate to the plasma membrane to induce cell rupture either by recruiting Ca 2+ and Na + ion channels to disrupt the balance between intracellular and extracellular osmotic pressures 11 or by directly disintegrating the membrane through the pore structure of the oligomer. 12 In addition to RIPK1, two more proteins with RHIM domains, Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) and toll-interleukin-1 receptor (TIR)-domaincontaining adapter-inducing interferon (TRIF), function upstream of RIPK3, interacting with RIPK3 via their RHIM domains to mediate necroptosis in response to viral infections and TLR signaling, respectively.…”

Section: Introductionmentioning

confidence: 99%

Role of Necroptosis in Central Nervous System Diseases

Shao

Wang

et al. 2022

ACS Chem. Neurosci.

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Necroptosis is a type of precisely regulated necrotic cell death activated in caspase-deficient conditions. Multiple factors initiate the necroptotic signaling pathway, including toll-like receptor 3/4, tumor necrosis factor (TNF), dsRNA viruses, and T cell receptors. Presently, TNF-induced necroptosis via the phosphorylation of three key proteins, receptor-interacting protein kinase 1, receptor-interacting protein kinase 3, and mixed lineage kinase domain-like protein, is the best-characterized process. Necroptosis induced by Z-DNA-binding protein 1 (ZBP-1) and toll/interleukin-1 receptor (TIR)-domain-containing adapter-inducing interferon (TRIF) plays a significant role in infectious diseases, such as influenza A virus, Zika virus, and herpesvirus infection. An increasing number of studies have demonstrated the close association of necroptosis with multiple diseases, and disrupting necroptosis has been confirmed to be effective for treating (or managing) these diseases. The central nervous system (CNS) exhibits unique physiological structures and immune characteristics. Necroptosis may occur without the sequential activation of signal proteins, and the necroptosis of supporting cells has more important implications in disease development. Additionally, necroptotic signals can be activated in the absence of necroptosis. Here, we summarize the role of necroptosis and its signal proteins in CNS diseases and characterize typical necroptosis regulators to provide a basis for the further development of therapeutic strategies for treating such diseases. In the present review, relevant information has been consolidated from recent studies (from 2010 until the present), excluding the patents in this field.

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Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia

Cited by 25 publications

References 74 publications

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

DUSP2-mediated inhibition of tubular epithelial cell pyroptosis confers nephroprotection in acute kidney injury

Ferroptosis, necroptosis, and pyroptosis in the occurrence and development of ovarian cancer

Role of Necroptosis in Central Nervous System Diseases

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