The ATF6 branch of unfolded protein response and apoptosis are activated to promote African swine fever virus infection

Galindo, I; Hernáez, B; Muñoz-Moreno, R; Cuesta-Geijo, M A; Dalmau-Mena, I; Alonso, C

African swine fever virus (ASFV) is a double-stranded large DNA virus that induces an acute disease of swine in which apoptosis has a central role in pathogenesis. Virus infection elicits apoptosis in target and immune defense cells. 1 The large repertoire of anti-apoptotic proteins encoded by the virus reflects the relevance of apoptosis in limiting viral replication in host cells. Many DNA viruses encode structural and functional homologs of anti-apoptotic Bcl-2 proteins, named viral Bcl2, including the A179L gene of ASFV. 2 In common with other viruses, ASFV has several strategies to block apoptotic pathways in order to complete virus replication. ASFV encodes proteins involved in apoptosis inhibition, thereby delaying the final execution step of the apoptotic pathway, which occurs only at late post-infection times. Programmed cell death itself may be relevant for the final release of virus particles within apoptotic bodies, which would provide this virus with a mechanism to spread, thus evading the immune system. The central component of the apoptotic machinery is the caspase proteolytic system. There are two groups of caspases: upstream initiator caspases, such as caspases 8 and 9, which cleave and activate other caspases; and downstream effector caspases, including caspase 3, which cleave a variety of cellular substrates, thereby disassembling cellular structures or inactivating enzymes. 3 Caspase 12 is associated with the cytoplasmic face of the endoplasmic reticulum (ER) and it cleaves to an active form in response to ER stress. 4 The ER stress response, also called the unfolded protein response (UPR), is mediated by three transmembrane proteins: (i) the protein kinase-like ER resident kinase (PERK); (ii) the activating transcription factor 6 (ATF6); and (iii) the inositol-requiring enzyme 1 (IRE1). 5 These three proteins are associated with the ER chaperone BiP/Grp78, which prevents their aggregation and further activation. However, when misfolded proteins accumulate, BiP is released, thus allowing UPR activation. Activated PERK phosphorylates the eukaryotic initiation factor 2a (eIF2a), thus resulting in translation attenuation to counterbalance enhanced protein accumulation. This counterbalancing effect includes the upregulation of the pro-apoptotic mRNA CHOP (c/EBP homologous protein) and mRNA encoding GADD34 (growth arrest and DNA-damage-inducible protein-34), whose association with the protein phosphatase 1 (PP1) leads to the dephosphorylation of eIF2a. 5 Activated IRE1 removes 26 nucleotides from X-box binding protein-1 (XBP1) mRNA, thereby altering the open reading frame and causing the translation of an active transcription factor. 6 The spliced form of XBP1 protein (sXBP1) is involved in the transcriptional activation of a number of genes, including the ER mannosidase-like protein EDEM, which participates in protein degradation. Finally, activated ATF6 exits ER compartment to migrate to the Golgi apparatus where it is cleaved by proteases. 7 ATF6 cytosolic fragment is a transcription factor responsible for the transcriptional induction of XBP1 as well as many ER chaperone-encoding genes. 5 However, when cells are unable to recover from ER stress, apoptosis occurs.