Ubiquitylation of RIPK3 beyond-the-RHIM can limit RIPK3 activity and cell death

Frank, D; Garnish, SE; Sandow, JJ; Weir, A; Liu, L; Clayer, E; Meza, L; Rashidi, M; Cobbold, SA; Scutts, SR; Doerflinger, M; Anderton, H; Lawlor, KE; Lalaoui, N; Kueh, AJ; Eng, VV; Ambrose, RL; Herold, MJ; Samson, AL; Feltham, R; Murphy, JM; Ebert, G; Pearson, JS; Vince, JE

Author(s): Frank, D; Garnish, SE; Sandow, JJ; Weir, A; Liu, L; Clayer, E; Meza, L; Rashidi, M; Cobbold, SA; Scutts, SR; Doerflinger, M; Anderton, H; Lawlor, KE; Lalaoui, N; Kueh, AJ; Eng, VV; Ambrose, RL; Herold, MJ; Samson, AL; Feltham, R; Murphy, JM; Ebert, G; Pearson, JS; Vince, JE;
Details: Publication Year 2022-07-15,Volume 25,Issue #7,Page 104632
Journal Title: iScience
Abstract: Pathogen 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. Ripk3 (K469R/K469R) mice challenged with Salmonella displayed enhanced bacterial loads and reduced serum IFNγ. However, Ripk3 (K469R/K469R) macrophages 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.
Publisher: Elsevier
Keywords: Cell biology; Molecular biology
Research Division(s): Inflammation; Blood Cells And Blood Cancer; Advanced Technology And Biology; Infectious Diseases And Immune Defence; Ubiquitin Signalling
PubMed ID: 35800780
Publisher's Version: https://doi.org/10.1016/j.isci.2022.104632
Open Access at Publisher's Site: https://doi.org/10.1016/j.isci.2022.104632
Terms of Use/Rights Notice: Refer to copyright notice on published article.
Documents: Frank D et al_iScience_2022.pdf - (5.18MB, application/pdf)

Creation Date: 2022-07-11 12:21:22

Last Modified: 2022-07-11 12:28:09