Phylogenetically Distant Viruses Use the Same BH3-Only Protein Puma to Trigger Bax/Bak-Dependent Apoptosis of Infected Mouse and Human Cells

Abstract

Viruses can trigger apoptosis of infected host cells if not counteracted by cellular or viral anti-apoptotic proteins. These protective proteins either inhibit the activation of caspases or they act as Bcl-2 homologs to prevent Bax/Bak-mediated outer mitochondrial membrane permeabilization (MOMP). The exact mechanism by which viruses trigger MOMP has however remained enigmatic. Here we use two distinct types of viruses, a double stranded DNA virus, herpes simplex virus-1 (HSV-1) and a positive sense, single stranded RNA virus, Semliki Forest virus (SFV) to show that the BH3-only protein Puma is the major mediator of virus-induced Bax/Bak activation and MOMP induction. Indeed, when Puma was genetically deleted or downregulated by shRNA, mouse embryonic fibroblasts and IL-3-dependent monocytes as well as human colon carcinoma cells were as resistant to virus-induced apoptosis as their Bax/Bak double deficient counterparts (Bax/Bak-/-). Puma protein expression started to augment after 2 h postinfection with both viruses. Puma mRNA levels increased as well, but this occurred after apoptosis initiation (MOMP) because it was blocked in cells lacking Bax/Bak or overexpressing Bcl-xL. Moreover, none of the classical Puma transcription factors such as p53, p73 or p65 NFκB were involved in HSV-1-induced apoptosis. Our data suggest that viruses use a Puma protein-dependent mechanism to trigger MOMP and apoptosis in host cells.

HSV-1-induced activation of NF-κB protects U937 monocytic cells against both virus replication and apoptosis

“… 5 , 37 Furthermore, we recently reported that cells that expressed a dominant negative (DN) form of I κ Bα displayed high levels of apoptosis when infected with wild type HSV-1. 31 These results support a role for NF- κ B activation in preventing apoptosis during HSV infection that can vary with respect to the context and the ability of the cells to sustain virus replication. Thus, resolving the intricate interplay between NF- κ B signalling, apoptosis and HSV-1 replication remains an intriguing issue to better understand the complex processes controlling HSV infectious cycle and the restriction of infection in some cell types.…”

“…Interestingly, we have recently demonstrated that apoptosis by HSV-1 in monocytic cells depends on Bax/Bak and the BH3-only Puma protein. 31 In addition, Bcl-2 overexpression in U937 monocytic cells infected with HSV-1 31 or HSV-2 32 leads to an increase of virus yield, further supporting the notion that virus replication in this cell type can be strongly affected by modulating the apoptotic pathway.…”

“…The paradigm in virus infection is that levels of virus replication should be inversely correlated with levels of apoptosis, as we previously observed in Bcl-2 overexpressing U937 cells infected with HSV-2 32 and in a less pronounced manner with HSV-1. 31 Given that disruption of NF- κ B activation enhanced HSV-1 replication in monocytic cells we could expect that levels of apoptosis should be concomitantly diminished. However, NF- κ B is considered a survival factor and prevention of its activation should enhance apoptosis.…”

The etiology of Bell’s palsy: a review

“…A possible cause of HSV-1-mediated neural dysfunction is the activation of apoptotic pathways and intra-axonal degradation, which are driven by the axon's local indirect and direct responses to the viruses themselves in susceptible phenotypes. Studies have suggested that viruses use abnormal expressions of p53 upregulated modulator of apoptosis (PUMA) [30] and/or innate immunity signaling molecule (SARM1) [31,32] to trigger axon degeneration. This implies that PUMA and/or SARM may play an important role in HSV-1-mediated neural dysfunction.…”

Purified vitexin compound 1, a new neolignan isolated compound, promotes PUMA‐dependent apoptosis in colorectal cancer

“…The activation of PUMA by nongenotoxic stimuli is p53‐independent and mediated by different transcription factors, including p53 homologue p73, forkhead box O3a (FoxO3a), and nuclear factor‐kappa B (NF‐κB) . Upon induction, PUMA facilitates mitochondrial outer membrane permeabilization and caspase activation cascade to regulate Bcl‐2‐associated X protein (Bax) activity . PUMA‐deficient colorectal cancer cells eliminate mitochondrial apoptosis caused by various stimuli .…”