PRMT5-mediated regulatory arginine methylation of RIPK3

Chauhan, Chanchal; Martínez-Val, Ana; Niedenthal, Rainer; Olsen, Jesper V.; Kotlyarov, Alexey; Bekker‐Jensen, Simon; Gaestel, Matthias; Menon, Manoj B.

doi:10.1038/s41420-023-01299-z

Cited by 4 publications

(2 citation statements)

References 58 publications

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“…Indeed, our study has found that found a decrease in PRMT5 expression in patients with IBD, and mice lacking PRMT5 in IECs spontaneously develop severe intestinal inflammation. A previous study reported RIP3 as a target protein of PRMT5 through mass spectrometry screening of cellular proteins (Chauhan et al, 2023), but there was no evidence to prove its existence in vivo or clarify the precise mechanism by which di-methylation of RIP3 activates necroptosis. In this study, we demonstrated that di-methylation-mediated activation of IECs necroptosis by RIP3 led to early death in Prmt5- deficient mice.…”

Section: Discussionmentioning

confidence: 99%

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

Zhao,

Dan,

Wang

et al. 2024

Preprint

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The necroptosis mediated by RIPK3 is stringently regulated for intestinal homeostasis. Here we found that mice lackingPrmt5(Protein arginase methyltransferase 5) in intestinal epithelial cells (IECs) caused premature death with IECs necroptosis, villus atrophy and loss of Paneth cells. This pathology can be partially rescued by antibiotic treatment, germ-free breeding condition and pharmaceutical inhibition of RIPK1 and RIPK3, but aggravated for embryonic lethality byCaspase-8 deficiency, which demonstrating the importance of commensal bacteria and necroptosis for thePrmt5-IEC deficiency. Intriguingly, tumor-necrosis factor (TNF) receptor 1(Tnfr1) deficiency could not completely rescue the pathology, and mice deficit in Z- DNA binding protein 1(ZBP1) exhibited shorter lifespan compared withPrmt5null mice, suggestingPrmt5loss might trigger TNFR-RIPK1-depenfent and ZBP1- dependent necroptosis. Mechanically, we identified the 479-arginine residue of RIPK3 di-methylated by PRMT5 was an endogenous checkpoint for necroptosis. Furthermore, RIPK3-R479K mutation had higher affinity with both RIPK1 and ZBP1 by immunoprecipitation and STORM (Stochastic Optical Reconstruction Microscopy) analysis, which might explain the endogenous necroptosis triggered by mutated RIPK3 even without upstream stimuli. Moreover, the peptide of RIPK3-SDMA (Symmetric dimethylarginine of 479) could rescue lethality ofPrmt5 lacking mice through necrosome formation inhibition, which demonstrating the great potential for necroptosis-related disease treatment through RIPK3 dimethylation targeting.

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Section: Discussionmentioning

confidence: 99%

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

Zhao,

Dan,

Wang

et al. 2024

Preprint

View full text Add to dashboard Cite

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“…However, we do not exclude that the other PRMTs can act on various components of the extrinsic cell death network by inducing mono- and di-methylation on arginine residues. In this context, it should be mentioned that arginine methylation of RIPK3 by PRMT5 has recently been described, and that methylation of c-FLIP L by PRMT5 and PRMT1 has been reported to be important for c-FLIP L degradation [ 46 , 47 ]. The further role of arginine methylation in extrinsic cell death pathways needs to be addressed in future studies.…”

Section: Discussionmentioning

confidence: 99%

Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks

Wohlfromm,

Ivanisenko,

Pietkiewicz

et al. 2024

Oncogene

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Procaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex. Furthermore, two potential methylation sites of PRMT5 on procaspase-8, R233 and R435, were identified in silico. R233 and R435 are highly conserved in mammals and their point mutations are among the most common mutations of caspase-8 in cancer. The introduction of mutations at these positions resulted in inhibitory effects on CD95L-induced caspase-8 activity, effector caspase activation and apoptosis. In addition, we show that procaspase-8 can undergo symmetric di-methylation. Finally, the pharmacological inhibition of PRMT5 resulted in the inhibitory effects on caspase activity and apoptotic cell death. Taken together, we have unraveled the additional control checkpoint in procaspase-8 activation and the arginine methylation network in the extrinsic apoptosis pathway.

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Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis

Liao,

Li,

Kang

et al. 2024

Nat Commun

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Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with dismal prognosis due to distant metastasis, even in the early stage. Using RNA sequencing and multiplex immunofluorescence, here we find elevated expression of mixed lineage kinase domain-like pseudo-kinase (MLKL) and enhanced necroptosis pathway in PDAC from early liver metastasis T-stage (T1M1) patients comparing with non-metastatic (T1M0) patients. Mechanistically, MLKL-driven necroptosis recruits macrophages, enhances the tumor CD47 ‘don’t eat me’ signal, and induces macrophage extracellular traps (MET) formation for CXCL8 activation. CXCL8 further initiates epithelial–mesenchymal transition (EMT) and upregulates ICAM-1 expression to promote endothelial adhesion. METs also degrades extracellular matrix, that eventually supports PDAC liver metastasis. Meanwhile, targeting necroptosis and CD47 reduces liver metastasis in vivo. Our study thus reveals that necroptosis facilitates PDAC metastasis by evading immune surveillance, and also suggest that CD47 blockade, combined with MLKL inhibitor GW806742X, may be a promising neoadjuvant immunotherapy for overcoming the T1M1 dilemma and reviving the opportunity for radical surgery.

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PRMT5-mediated regulatory arginine methylation of RIPK3

Cited by 4 publications

References 58 publications

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

Arginine Di-methylation of RIPK3 Safeguards Necroptosis for Intestinal Homeostasis

Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks

Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis

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