SARS-CoV-1 3a binds RIPK1:RIPK3 oligomer

Stable Identifier
Reaction [binding]
Homo sapiens
Related Species
Human SARS coronavirus
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Severe acute respiratory syndrome-associated coronavirus type 1 (SARS-CoV-1) 3a protein was shown to interact with receptor interacting protein kinase 3 (RIPK3) by immunoprecipitation analysis upon co-expression of viral 3a and RIPK3 in human embryonic kidney 293 (HEK293) cells (Yue Y et al. 2018). Mapping of the interaction between RIPK3 and 3a showed that the kinase domain of RIPK3 (1–326) interacted with SARS-CoV-1 3a, but that the RIP homotypic interaction motif (RHIM) containing C-terminus (327–518) interacted very weakly. Time-lapse confocal microscopy using Cherry-tagged RIP3 in HeLa cells expressing SARS-CoV-1 3a-GFP showed that expression of RIPK3 drives cell death in the presence of SARS 3a. Further, RIPK3-induced oligomerization of SARS-CoV-1 3a (studied with the oligomerization-deficient viral 3a-flag C133A mutant) helped drive necrotic cell death in RIPK3-expressing HEK293, HeLa and 5-Aza-2′-deoxycytidine (5-AD)-treated human alveolar epithelial A549 cells (Yue Y et al. 2018). The A549 cell line is resistant to the traditional necroptotic stimuli, but treatment with hypomethylating agents such as 5-AD induced RIPK3 expression (Yue Y et al. 2018). The results of the study suggest that SARS-Cov-1 3a does not induce cell death in the absence of RIPK3, but induces significant oligomerization-dependent death in the presence of endogenous RIPK3. (Yue Y et al. 2018).

During tumor necrosis factor (TNF)-induced necroptosis, RIPK3 and RIPK1 associate with each other through their RHIM domains into heteromeric RIPK1:RIPK3 complexes that further polymerize into filamentous β-amyloid structures promoting the activation of RIPK3 kinase (Cho Y et al. 2009; Li J et al. 2012). Functionally active RIPK3 activates mixed-lineage kinase domain-like pseudokinase (MLKL), the membrane-disrupting effector of programmed necrosis (Sun L et al. 2012; Murphy JM et al. 2013; Wang H et al. 2014). Other RHIM-containing proteins, such as the TLR3/TLR4 adaptor TRIF (also known as TICAM1) and the DNA sensor DAI/ZBP can form the necroptotic signaling platforms to support activation of RIPK3 and its interaction with MLKL (Kaiser W et al. 2013; Lin J et al. 2016).

This Reactome event shows a scaffolding role of RIPK3 bound to RIPK1 in supporting the formation of SARS-CoV-1 3a oligomers.

Literature References
PubMed ID Title Journal Year
30185776 SARS-Coronavirus Open Reading Frame-3a drives multimodal necrotic cell death

Yue, Y, Nabar, NR, Shi, CS, Kamenyeva, O, Xiao, X, Hwang, IY, Wang, M, Kehrl, JH

Cell Death Dis 2018
Name Identifier Synonyms
severe acute respiratory syndrome DOID:2945 SARS-CoV infection, SARS
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