Mechanisms of TNF-independent RIPK3-mediated cell death

Tummers, Bart; Green, Douglas R.

doi:10.1042/bcj20210724

Cited by 11 publications

(5 citation statements)

References 139 publications

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“…It is known that RIPK1 can interact with RIPK3 through the RHIM domain and trigger auto‐ and transphosphorylation of RIPK3 41 . It has been demonstrated that activated RIPK3 can induce both necroptosis and apoptosis, 42 although, in our system, RIPK3 inhibition did not alter cell response to 5‐FU or OxaPt.…”

Section: Discussioncontrasting

confidence: 58%

The role of p62 in cell death and survival of 5‐fluorouracil and oxaliplatin‐resistant colorectal cancer cells

Zitkute,

Jasinevicius,

Vaitiekaite

et al. 2023

J of Cellular Biochemistry

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The protein sequestosome 1 (p62/SQSTM1) is primarily known as a selective autophagy cargo receptor, but due to its multidomain structure, it also has roles in the ubiquitin‐proteasome system, metabolism, cell death and survival signalling. The increase in p62 levels is detected in some types of cancers, including colorectal cancer (CRC). Chemoresistance is the main cause of high mortality rates of CRC patients. Since p62 can regulate both cell survival and death, it is a potential modulator of chemoresistance. The impact of p62 on molecular causes of chemoresistance in CRC cells is insufficiently analysed. Therefore, we aimed to determine the impact of p62 on apoptosis, RIPK1‐pRIPK3 axis, and IL‐8 levels in chemoresistant CRC cells. Our data revealed that p62 levels are higher in the 5‐fluorouracil (5‐FU)‐resistant HCT116/FU subline compared to the parental cell line. 5‐FU and oxaliplatin (OxaPt) treatment decreased p62 protein levels and it correlated with chemoresistance of HCT116 and DLD1 cell lines. The silencing of p62 increased CRC cell sensitivity to 5‐FU and OxaPt, hence p62 is one of the factors supporting chemoresistance. The downregulation of p62 reduced the activation of caspase‐3 and the levels of RIPK1 and pRIPK3. Furthermore, p62 silencing decreased the BAX/BCL2 ratio in the HCT116/FU subline and did not change the levels of apoptosis. Instead, p62 silencing reduced the amount of IL‐8 protein. Our results show that p62 impacts chemoresistance by stimulating prosurvival signalling.

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Section: Discussioncontrasting

confidence: 58%

The role of p62 in cell death and survival of 5‐fluorouracil and oxaliplatin‐resistant colorectal cancer cells

Zitkute,

Jasinevicius,

Vaitiekaite

et al. 2023

J of Cellular Biochemistry

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“…Like apoptosis, PKR-mediated necroptosis can occur in response to IFNs, possibly requiring PKR interaction with RIPK1 [ 113 ]. While other groups have also observed a physical association between PKR and RIPK1 [ 143 ], the exact role that PKR plays in initiating necroptosis in response to IFN stimulation remains unclear [ 144 ]. Notably it has been proposed that IFN-stimulated PKR-mediated necroptosis is restricted to the G2M stage of the cell cycle, when FADD is disabled, preventing capase-8 inhibition of necrosome formation [ 113 ].…”

Section: Resultsmentioning

confidence: 99%

Susceptibility and Permissivity of Zebrafish (Danio rerio) Larvae to Cypriniviruses

Streiff

Morvan

et al. 2023

Viruses

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The zebrafish (Danio rerio) represents an increasingly important model organism in virology. We evaluated its utility in the study of economically important viruses from the genus Cyprinivirus (anguillid herpesvirus 1, cyprinid herpesvirus 2 and cyprinid herpesvirus 3 (CyHV-3)). This revealed that zebrafish larvae were not susceptible to these viruses after immersion in contaminated water, but that infections could be established using artificial infection models in vitro (zebrafish cell lines) and in vivo (microinjection of larvae). However, infections were transient, with rapid viral clearance associated with apoptosis-like death of infected cells. Transcriptomic analysis of CyHV-3-infected larvae revealed upregulation of interferon-stimulated genes, in particular those encoding nucleic acid sensors, mediators of programmed cell death and related genes. It was notable that uncharacterized non-coding RNA genes and retrotransposons were also among those most upregulated. CRISPR/Cas9 knockout of the zebrafish gene encoding protein kinase R (PKR) and a related gene encoding a protein kinase containing Z-DNA binding domains (PKZ) had no impact on CyHV-3 clearance in larvae. Our study strongly supports the importance of innate immunity-virus interactions in the adaptation of cypriniviruses to their natural hosts. It also highlights the potential of the CyHV-3-zebrafish model, versus the CyHV-3-carp model, for study of these interactions.

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“…While unexpected, such a response could be important against severe pathogens that disarm RhoA, the key upstream activator of ROCK1, since it could enable B cells to recruit and organize an inflammatory infiltrate and "jump-start" responses during these infections. Surprisingly, the enhanced proinflammatory capabilities of ROCK1-deficient B cells were accompanied by the dysregulated assembly of p62 complexes containing key ripoptosome components, ZBP1, RIPK1, and RIPK3, long implicated in the orchestration of inflammatory responses and necroptosis in innate cells 52 but whose role in B cells is largely unexplored.…”

Section: Discussionmentioning

confidence: 99%

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

Rivera-Correa,

Gupta,

Ricker

et al. 2023

Preprint

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Protective humoral responses require that B cells successfully complete their differentiation programs even when exposed to hostile environments generated during severe infections, like the massive hemolysis triggered by malaria. The mechanisms utilized by differentiating B cells to withstand damaging conditions replete in PAMPs and DAMPs are poorly understood. Here we demonstrate that the serine-threonine kinase ROCK1 enables B cells to execute their differentiation programs upon exposure to PAMPs and high levels of heme, a critical DAMP, by controlling two key heme-regulated molecules, Bach2 and HRI. ROCK1 restrains plasma cell differentiation by phosphorylating Bach2. As B cells differentiate in the presence of PAMPs and heme, furthermore, ROCK1 limits the proinflammatory potential of B cells and restrains mTORC1 activity by controlling the assembly of multimolecular complexes that contain the adaptor p62, raptor, ripoptosome components, and molecules involved in RNA metabolism and proteostasis. ROCK1 regulates formation of these complexes by controlling the interplay between HSPs and the stress kinase HRI. Thus, ROCK1 helps B cells cope with intense pathogen-driven destruction by coordinating the activity and localization of key molecules that mediate cell-fate decisions, effector functions, and RNA and protein homeostasis. These ROCK1-dependent mechanisms may be widely employed by cells to handle severe environmental stresses and these findings may be broadly relevant for infections, vaccine development, and immune-mediated diseases marked by chronic tissue damage like autoimmune disorders.

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Mechanisms of TNF-independent RIPK3-mediated cell death

Cited by 11 publications

References 139 publications

The role of p62 in cell death and survival of 5‐fluorouracil and oxaliplatin‐resistant colorectal cancer cells

The role of p62 in cell death and survival of 5‐fluorouracil and oxaliplatin‐resistant colorectal cancer cells

Susceptibility and Permissivity of Zebrafish (Danio rerio) Larvae to Cypriniviruses

ROCK1 orchestrates B cell differentiation in response to PAMPs and heme by controlling the heme-regulated proteins Bach2 and HRI

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