Pore-forming neurons: a new paradigm of pyroptotic cell death in HIV-associated neurocognitive disorder

Abstract

This scientific commentary refers to ‘Caspase cleavage of gasdermin E causes neuronal pyroptosis in HIV-associated neurocognitive disorder’ by Fernandes et al. (https://doi.org/10.1093/brain/awad375).

Figure 1

Viral protein R-mediated neuronal pyroptosis. Exposure of neurons to HIV-1 viral protein R (Vpr) triggers activation of the NLRP3 protein, culminating in the formation of the NLRP3 inflammasome complex, which also comprises apoptosis-associated speck-like protein containing a CARD (ASC) and procaspase-1. Activation of this multiprotein complex induces cleavage of caspase-1, leading to the activation of caspase-3, while also facilitating the cleavage of the proinflammatory cytokines IL-1β and IL-18 into their mature forms. The caspase-1 inhibitor VX-765 intervenes in the pathway by blocking downstream events associated with cleaved caspase-1. Activated caspase-3 targets PARP1 and full-length (FL) GSDME in neurons. The cleaved N-terminal fragment of GSDME, in turn, induces pore formation in the neuronal plasma membrane, an action that is exacerbated by the induction of NINJ1. This leads to nuclear disintegration, with the release of mature proinflammatory cytokines and neuronal pyroptotic death.