Viral proteins targeting mitochondria: controlling cell death

Abstract

Mitochondrial membrane permeabilization (MMP) is a critical step regulating apoptosis. Viruses have evolved multiple strategies to modulate apoptosis for their own benefit. Thus, many viruses code for proteins that act on mitochondria and control apoptosis of infected cells. Viral proapoptotic proteins translocate to mitochondrial membranes and induce MMP, which is often accompanied by mitochondrial swelling and fragmentation. From a structural point of view, all the viral proapoptotic proteins discovered so far contain amphipathic alpha-helices that are necessary for the proapoptotic effects and seem to have pore-forming properties, as it has been shown for Vpr from human immunodeficiency virus-1 (HIV-1) and HBx from hepatitis B virus (HBV). In contrast, antiapoptotic viral proteins (e.g., M11L from myxoma virus, F1L from vaccinia virus and BHRF1 from Epstein-Barr virus) contain mitochondrial targeting sequences (MTS) in their C-terminus that are homologous to tail-anchoring domains. These domains are similar to those present in many proteins of the Bcl-2 family and are responsible for inserting the protein in the outer mitochondrial membrane leaving the N-terminus of the protein facing the cytosol. The antiapoptotic proteins K7 and K15 from avian encephalomyelitis virus (AEV) and viral mitochondria inhibitor of apoptosis (vMIA) from cytomegalovirus are capable of binding host-specific apoptosis-modulatory proteins such as Bax, Bcl-2, activated caspase 3, CAML, CIDE-B and HAX. In conclusion, viruses modulate apoptosis at the mitochondrial level by multiple different strategies.

To kill or be killed: how HIV exhausts the immune system

“…77,78 Like many other viruses, HIV codes for proteins that act on mitochondria and control apoptosis of infected cells. 79 For example, Vpr causes a rapid dissipation of the mitochondrial transmembrane potential in intact cells, as well as the release of cytochrome c and cellular apoptosis. 65 Like other viral proapoptotic proteins, such as HBx coded by HBV, Vpr contains amphipatic a helices that are necessary for the proapoptotic effect and seem to have poreforming properties.…”

“…65 Like other viral proapoptotic proteins, such as HBx coded by HBV, Vpr contains amphipatic a helices that are necessary for the proapoptotic effect and seem to have poreforming properties. 79 Tat induces apoptosis by downregulating Bcl-2 62 and upregulating caspase-8, 61 and the binding of HIV gp120 to CD4 receptor on previously activated cells induces the downregulation of Bcl-2 53 promoting the release of cytochrome c. 80 Proteolytic degradation of Bcl-2 can also be the consequence of the activation of caspase-8 by HIV protease. 74 In order to efficiently disseminate, HIV also needs to inhibit cellular apoptosis of the host cell, at least until high levels of progeny virus are produced, like many other viruses do.…”

Lysosomal membrane permeabilization in cell death

“…A range of different viral proteins kill infected cells by facilitating the induction of MOMP (Boya et al, 2004). In addition, several viral proteins such as Nef from human immunodeficiency virus-1, protein U7 from human papillomavirus type-16, parvovirus H1 and herpes simplex virus infection induce LMP-and cathepsin-dependent cell death (Kaznelson et al, 2004;Di Piazza et al, 2007;Laforge et al, 2007).…”

Apoptosis induced by Semliki Forest virus is RNA replication dependent and mediated via Bak

“…15 For DNA viruses, virally encoded survival factors of the Bcl-2 family or proteins interfering with death receptor signalling have helped to dissect the death signalling pathways in host cells. 16,17 By contrast, RNA viruses usually do not encode survival factors in their genome, and hence uncovering the relevant death signalling components has been more difficult. [18][19][20][21][22][23][24] Here, we show that SFV requires an intact RNA genome and a Bak/ mitochondria-mediated signalling pathway for apoptosis induction.…”