文章基本信息

标题：Ubiquitylation of RIPK3 beyond-the-RHIM can limit RIPK3 activity and cell death
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作者：Daniel Frank ; Sarah E. Garnish ; Jarrod J. Sandow 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：7
页码：1-29
DOI：10.1016/j.isci.2022.104632
语种：English
出版社：Elsevier
摘要：SummaryPathogen recognition and TNF receptors signal via receptor interacting serine/threonine kinase-3 (RIPK3) to cause cell death, including MLKL-mediated necroptosis and caspase-8-dependent apoptosis. However, the post-translational control of RIPK3 is not fully understood. Using mass-spectrometry, we identified that RIPK3 is ubiquitylated on K469. The expression of mutant RIPK3 K469R demonstrated that RIPK3 ubiquitylation can limit both RIPK3-mediated apoptosis and necroptosis. The enhanced cell death of overexpressed RIPK3 K469R and activated endogenous RIPK3 correlated with an overall increase in RIPK3 ubiquitylation.Ripk3K469R/K469Rmice challenged withSalmonelladisplayed enhanced bacterial loads and reduced serum IFNγ. However,Ripk3K469R/K469Rmacrophages and dermal fibroblasts were not sensitized to RIPK3-mediated apoptotic or necroptotic signaling suggesting that, in these cells, there is functional redundancy with alternate RIPK3 ubiquitin-modified sites. Consistent with this idea, the mutation of other ubiquitylated RIPK3 residues also increased RIPK3 hyper-ubiquitylation and cell death. Therefore, the targeted ubiquitylation of RIPK3 may act as either a brake or accelerator of RIPK3-dependent killing.Graphical abstractDisplay OmittedHighlights•RIPK3 can be ubiquitylated on K469 to limit RIPK3-induced necroptosis and apoptosis•Ripk3K469R/K469Rmice are more susceptible toSalmonellainfection•Several ubiquitylated or surface exposed lysines can limit RIPK3-induced cell death•Hyper-ubiquitylated RIPK3 correlates with RIPK3 signaling and cell deathMolecular biology; Cell biology