scholarly journals Cytomegalovirus M45 Cell Death Suppression Requires Receptor-interacting Protein (RIP) Homotypic Interaction Motif (RHIM)-dependent Interaction with RIP1

2008 ◽  
Vol 283 (25) ◽  
pp. 16966-16970 ◽  
Author(s):  
Jason W. Upton ◽  
William J. Kaiser ◽  
Edward S. Mocarski
Keyword(s):  
Cell Death ◽  
Interacting Protein ◽  
Homotypic Interaction ◽  
Dependent Interaction

scholarly journals MLKL forms disulfide bond-dependent amyloid-like polymers to induce necroptosis

2017 ◽  
Vol 114 (36) ◽  
pp. E7450-E7459 ◽  
Author(s):  
Shuzhen Liu ◽  
Hua Liu ◽  
Andrea Johnston ◽  
Sarah Hanna-Addams ◽  
Eduardo Reynoso ◽  
...  
Keyword(s):  
Cell Death ◽  
Disulfide Bond ◽  
Kinase Domain ◽  
Proteinase K ◽  
Interacting Protein ◽  
Tnf Α ◽  
Mouse Cells ◽  
Red Dye ◽  
Necessary And Sufficient ◽  
Human And Mouse

Mixed-lineage kinase domain-like protein (MLKL) is essential for TNF-α–induced necroptosis. How MLKL promotes cell death is still under debate. Here we report that MLKL forms SDS-resistant, disulfide bond-dependent polymers during necroptosis in both human and mouse cells. MLKL polymers are independent of receptor-interacting protein kinase 1 and 3 (RIPK1/RIPK3) fibers. Large MLKL polymers are more than 2 million Da and are resistant to proteinase K digestion. MLKL polymers are fibers 5 nm in diameter under electron microscopy. Furthermore, the recombinant N-terminal domain of MLKL forms amyloid-like fibers and binds Congo red dye. MLKL mutants that cannot form polymers also fail to induce necroptosis efficiently. Finally, the compound necrosulfonamide conjugates cysteine 86 of human MLKL and blocks MLKL polymer formation and subsequent cell death. These results demonstrate that disulfide bond-dependent, amyloid-like MLKL polymers are necessary and sufficient to induce necroptosis.

scholarly journals Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2368-2375 ◽  
Author(s):  
Guilherme B. Fortes ◽  
Leticia S. Alves ◽  
Rosane de Oliveira ◽  
Fabianno F. Dutra ◽  
Danielle Rodrigues ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Critical Role ◽  
Membrane Integrity ◽  
Iron Chelation ◽  
Heme Oxygenase 1 ◽  
Cytotoxic Effects ◽  
Interacting Protein ◽  
Free Heme ◽  
Necrosis Factor

Abstract Diseases that cause hemolysis or myonecrosis lead to the leakage of large amounts of heme proteins. Free heme has proinflammatory and cytotoxic effects. Heme induces TLR4-dependent production of tumor necrosis factor (TNF), whereas heme cytotoxicity has been attributed to its ability to intercalate into cell membranes and cause oxidative stress. We show that heme caused early macrophage death characterized by the loss of plasma membrane integrity and morphologic features resembling necrosis. Heme-induced cell death required TNFR1 and TLR4/MyD88-dependent TNF production. Addition of TNF to Tlr4−/− or to Myd88−/− macrophages restored heme-induced cell death. The use of necrostatin-1, a selective inhibitor of receptor-interacting protein 1 (RIP1, also known as RIPK1), or cells deficient in Rip1 or Rip3 revealed a critical role for RIP proteins in heme-induced cell death. Serum, antioxidants, iron chelation, or inhibition of c-Jun N-terminal kinase (JNK) ameliorated heme-induced oxidative burst and blocked macrophage cell death. Macrophages from heme oxygenase-1 deficient mice (Hmox1−/−) had increased oxidative stress and were more sensitive to heme. Taken together, these results revealed that heme induces macrophage necrosis through 2 synergistic mechanisms: TLR4/Myd88-dependent expression of TNF and TLR4-independent generation of ROS.

scholarly journals The lysosomal Rag-Ragulator complex licenses RIPK1– and caspase-8–mediated pyroptosis by Yersinia

Science ◽  
2021 ◽  
Vol 372 (6549) ◽  
pp. eabg0269
Author(s):  
Zengzhang Zheng ◽  
Wanyan Deng ◽  
Yang Bai ◽  
Rui Miao ◽  
Shenglin Mei ◽  
...  
Keyword(s):  
Cell Death ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Host Cells ◽  
Caspase 8 ◽  
Death Domain ◽  
Interacting Protein ◽  
A Genome ◽  
Infection Inhibition ◽  
Guanosine Triphosphatase

Host cells initiate cell death programs to limit pathogen infection. Inhibition of transforming growth factor–β–activated kinase 1 (TAK1) by pathogenic Yersinia in macrophages triggers receptor-interacting serine-threonine protein kinase 1 (RIPK1)–dependent caspase-8 cleavage of gasdermin D (GSDMD) and inflammatory cell death (pyroptosis). A genome-wide CRISPR screen to uncover mediators of caspase-8–dependent pyroptosis identified an unexpected role of the lysosomal folliculin (FLCN)–folliculin-interacting protein 2 (FNIP2)–Rag-Ragulator supercomplex, which regulates metabolic signaling and the mechanistic target of rapamycin complex 1 (mTORC1). In response to Yersinia infection, Fas-associated death domain (FADD), RIPK1, and caspase-8 were recruited to Rag-Ragulator, causing RIPK1 phosphorylation and caspase-8 activation. Pyroptosis activation depended on Rag guanosine triphosphatase activity and lysosomal tethering of Rag-Ragulator but not mTORC1. Thus, the lysosomal metabolic regulator Rag-Ragulator instructs the inflammatory response to Yersinia.

scholarly journals RIPK1 Is Cleaved by 3C Protease of Rhinovirus A and B Strains and Minor and Major Groups

Viruses ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2402
Author(s):  
Sarah N. Croft ◽  
Erin J. Walker ◽  
Reena Ghildyal
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Programmed Cell Death ◽  
Protease Inhibitor ◽  
Phylogenetic Groups ◽  
Viral Protease ◽  
Interacting Protein ◽  
3C Protease ◽  
Survival Pathways ◽  
Integral Role

Rhinoviruses (RV), like many other viruses, modulate programmed cell death to their own advantage. The viral protease, 3C has an integral role in the modulation, and we have shown that RVA-16 3C protease cleaves Receptor-interacting protein kinase-1 (RIPK1), a key host factor that modulates various cell death and cell survival pathways. In the current study, we have investigated whether this cleavage is conserved across selected RV strains. RIPK1 was cleaved in cells infected with strains representing diversity across phylogenetic groups (A and B) and receptor usage (major and minor groups). The cleavage was abrogated in the presence of the specific 3C protease inhibitor, Rupintrivir. Interestingly, there appears to be involvement of another protease (maybe 2A protease) in RIPK1 cleavage in strains belonging to genotype B. Our data show that 3C protease from diverse RV strains cleaves RIPK1, highlighting the importance of the cleavage to the RV lifecycle.

scholarly journals The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils

2018 ◽  
Vol 11 (546) ◽  
pp. eaao1716 ◽  
Author(s):  
Akshay A. D’Cruz ◽  
Mary Speir ◽  
Meghan Bliss-Moreau ◽  
Sylvia Dietrich ◽  
Shu Wang ◽  
...  
Keyword(s):  
Cell Death ◽  
Kinase Domain ◽  
Neutrophil Extracellular Trap ◽  
Human Neutrophils ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Dependent Activity ◽  
Mrsa Infection ◽  
Death Effector ◽  
Net Release

Neutrophil extracellular trap (NET) formation can generate short-term, functional anucleate cytoplasts and trigger loss of cell viability. We demonstrated that the necroptotic cell death effector mixed lineage kinase domain–like (MLKL) translocated from the cytoplasm to the plasma membrane and stimulated downstream NADPH oxidase–independent ROS production, loss of cytoplasmic granules, breakdown of the nuclear membrane, chromatin decondensation, histone hypercitrullination, and extrusion of bacteriostatic NETs. This process was coordinated by receptor-interacting protein kinase-1 (RIPK1), which activated the caspase-8–dependent apoptotic or RIPK3/MLKL-dependent necroptotic death of mouse and human neutrophils. Genetic deficiency of RIPK3 and MLKL prevented NET formation but did not prevent cell death, which was because of residual caspase-8–dependent activity. Peptidylarginine deiminase 4 (PAD4) was activated downstream of RIPK1/RIPK3/MLKL and was required for maximal histone hypercitrullination and NET extrusion. This work defines a distinct signaling network that activates PAD4-dependent NET release for the control of methicillin-resistant Staphylococcus aureus (MRSA) infection.

Genetic Regulation of RIPK1 and Necroptosis

2021 ◽  
Vol 55 (1) ◽  
pp. 235-263
Author(s):  
Daichao Xu ◽  
Chengyu Zou ◽  
Junying Yuan
Keyword(s):  
Cell Death ◽  
Protein Kinase ◽  
Genetic Regulation ◽  
Caspase 8 ◽  
Inflammatory Signaling ◽  
Interacting Protein ◽  
Multiple Factors ◽  
Cell Death Pathways ◽  
Upstream Regulator ◽  
Multiple Cell

The receptor-interacting protein kinase 1 (RIPK1) is recognized as a master upstream regulator that controls cell survival and inflammatory signaling as well as multiple cell death pathways, including apoptosis and necroptosis. The activation of RIPK1 kinase is extensively modulated by ubiquitination and phosphorylation, which are mediated by multiple factors that also control the activation of the NF-κB pathway. We discuss current findings regarding the genetic modulation of RIPK1 that controls its activation and interaction with downstream mediators, such as caspase-8 and RIPK3, to promote apoptosis and necroptosis. We also address genetic autoinflammatory human conditions that involve abnormal activation of RIPK1. Leveraging these new genetic and mechanistic insights, we postulate how an improved understanding of RIPK1 biology may support the development of therapeutics that target RIPK1 for the treatment of human inflammatory and neurodegenerative diseases.

scholarly journals SMAC mimetics induce autophagy-dependent apoptosis of HIV-1-infected macrophages

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Grant R. Campbell ◽  
Rachel K. To ◽  
Gang Zhang ◽  
Stephen A. Spector
Keyword(s):  
Cell Death ◽  
Hiv Infection ◽  
Cell Survival ◽  
Acute Hiv Infection ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Hiv Eradication ◽  
Smac Mimetics ◽  
Smac Mimetic ◽  
Latent Hiv

Abstract Human immunodeficiency type 1 (HIV)-infected macrophages (HIV-Mφ) are a reservoir for latent HIV infection and a barrier to HIV eradication. In contrast to CD4+ T cells, HIV-Mφ are resistant to the cytopathic effects of acute HIV infection and have increased expression of cell survival factors, including X-linked inhibitor of apoptosis (XIAP), baculoviral IAP repeat containing (BIRC) 2/cIAP1, beclin-1, BCL2, BCL-xl, triggering receptor expressed on myeloid cells 1, mitofusin (MFN) 1, and MFN2. DIABLO/SMAC mimetics are therapeutic agents that affect cancer cell survival and induce cell death. We found that DIABLO/SMAC mimetics (LCL-161, AT-406 (also known as SM-406 or Debio 1143), and birinapant) selectively kill HIV-Mφ without increasing bystander cell death. DIABLO/SMAC mimetic treatment of HIV-Mφ-induced XIAP and BIRC2 degradation, leading to the induction of autophagy and the formation of a death-inducing signaling complex on phagophore membranes that includes both pro-apoptotic or necroptotic (FADD, receptor-interacting protein kinase (RIPK) 1, RIPK3, caspase 8, and MLKL) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacologic inhibition of early stages of autophagy, but not late stages of autophagy, ablated this interaction and inhibited apoptosis. Furthermore, DIABLO/SMAC mimetic-mediated apoptosis of HIV-Mφ is dependent upon tumor necrosis factor signaling. Our findings thus demonstrate that DIABLO/SMAC mimetics selectively induce autophagy-dependent apoptosis in HIV-Mφ.

scholarly journals Impaired RIPK1 ubiquitination sensitizes mice to TNF toxicity and inflammatory cell death

2020 ◽  
Author(s):  
Matthias Kist ◽  
László G. Kőműves ◽  
Tatiana Goncharov ◽  
Debra L. Dugger ◽  
Charles Yu ◽  
...  
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Mapk Signaling ◽  
Embryonic Lethality ◽  
Mapk Activation ◽  
Interacting Protein ◽  
Signaling Complex ◽  
Ubiquitination Site ◽  
Lysine Residues ◽  
The Stability

Abstract Receptor-interacting protein 1 (RIP1; RIPK1) is a key regulator of multiple signaling pathways that mediate inflammatory responses and cell death. TNF-TNFR1 triggered signaling complex formation, subsequent NF-κB and MAPK activation and induction of cell death involve RIPK1 ubiquitination at several lysine residues including Lys376 and Lys115. Here we show that mutating the ubiquitination site K376 of RIPK1 (K376R) in mice activates cell death resulting in embryonic lethality. In contrast to Ripk1K376R/K376R mice, Ripk1K115R/K115R mice reached adulthood and showed slightly higher responsiveness to TNF-induced death. Cell death observed in Ripk1K376R/K376R embryos relied on RIPK1 kinase activity as administration of RIPK1 inhibitor GNE684 to pregnant heterozygous mice effectively blocked cell death and prolonged survival. Embryonic lethality of Ripk1K376R/K376R mice was prevented by the loss of TNFR1, or by simultaneous deletion of caspase-8 and RIPK3. Interestingly, elimination of the wild-type allele from adult Ripk1K376R/cko mice was tolerated. However, adult Ripk1K376R/cko mice were exquisitely sensitive to TNF-induced hypothermia and associated lethality. Absence of the K376 ubiquitination site diminished K11-linked, K63-linked, and linear ubiquitination of RIPK1, and promoted the assembly of death-inducing cellular complexes, suggesting that multiple ubiquitin linkages contribute to the stability of the RIPK1 signaling complex that stimulates NF-κB and MAPK activation. In contrast, mutating K115 did not affect RIPK1 ubiquitination or TNF stimulated NF-κB and MAPK signaling. Overall, our data indicate that selective impairment of RIPK1 ubiquitination can lower the threshold for RIPK1 activation by TNF resulting in cell death and embryonic lethality.

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