<i>Staphylococcus aureus</i> reprograms CASP8 (caspase 8) signaling to evade cell death and Xenophagy

Regulated cell death and xenophagy constitute fundamental cellular mechanisms against invading microorganisms. <i>Staphylococcus aureus</i>, a notorious pathogen, can invade and persist within host cells for extended periods. Here, we describe a novel mechanism by which <i>S. aureus</i> subverts these host defenses through the manipulation of the CASP8 (caspase 8) signaling pathway. Upon invasion, <i>S. aureus</i> triggers the assembly of a RIPK3 (receptor interacting serine/threonine kinase 3) complex to induce CASP8 autoprocessing. However, the bacterium inhibits CUL3 (cullin 3)-dependent K63-linked ubiquitination, leading to an atypical activation of CASP8. This non-canonical activation does not initiate the CASP8-CASP3 cascade but instead suppresses RIPK3-dependent necroptosis, a regulated cell death pathway typically activated when apoptosis fails. The resulting non-apoptotic, cleaved CASP8 redirects its enzymatic activity toward cleaving SQSTM1/p62, a selective macroautophagy/autophagy receptor, thus enabling <i>S. aureus</i> to evade antimicrobial xenophagy. The results of this study suggest that <i>S. aureus</i> reprograms the CASP8 signaling pathway from inducing cell death to preserving cell survival and inhibiting xenophagy, a critical strategy that supports its stealthy replication and persistence within host cells.<b>Abbreviations</b>: CASP3: caspase 3; CASP8: caspase 8; CFU: colony-forming units; CUL3: cullin 3; DUB: deubiquitinating enzyme; MAP1LC3B-II/LC3B-II: microtubule associated protein 1 light chain 3 beta-II; MOI: multiplicity of infection; RIPK1: receptor interacting protein kinase 1; RIPK3: receptor interacting protein kinase 3; <i>S. aureus</i>: <i>Staphylococcus aureus</i>.