kills BVDV-infected cells. Similarly, respiratory syncytial virus (RSV) infection causes ER stress, the cleavage and activation of caspase-12, and apoptosis in a lung epithelial cell line. An antisense construct against caspase12 reduced the number of apoptotic cells by almost four-fold, suggesting that caspase-12 is a critical component of RSV-induced apoptosis. Similarly, paramyxovirus induces the ESR, caspase-12 activation, and apoptosis, which can be blocked by a small molecule pan-inhibitor of all caspases, but not by specific inhibitors of non– caspase-12 family members, indicating that an ER stressspecific pathway is responsible for apoptosis in this system. An ER-specific apoptotic program may also be activated by hantavirus infection.

Although it is likely that ER stress is a common consequence of viral infection, it is not yet clear what role the resulting ESR may play in viral pathogenesis. Indeed, some components of the ESR, such as chaperone induction, might be expected to aid virus replication by facilitating the assembly of viral glycoproteins, while other pathways, such as PERK and caspase-12 activation, may hamper viral protein production or kill host cells, limiting the infection. Consistent with this idea, PERK is required for resistance to VSV infection, at least in cell culture. Additionally, HCV suppresses the IRE1/XBP-1 pathway, suggesting that blocking the UPRdriven induction of ERAD genes may promote viral replication by avoiding the ERAD-mediated degradation of viral proteins. On the other hand, some viruses may use ESR as an immune evasion strategy, as observed with cytomegalovirus, which co-opts ERAD to destroy major histocompatibility proteins and elude T-cell detection.

HSV provides another interesting example of the interplay between viral pathogenesis and the ESR. Recently, HSV was shown to induce protein synthesisdependent activation of PERK, which is potentiated in cells lacking PKR, the main infection-activated eIF2α kinase. This result suggests that multiple eIF2α kinases may cooperate in the response to HSV infection. Interestingly, HSV encodes ICP34.5, a homolog of GADD34 that binds to cellular PP1 and mediates eIF2α dephos-

phorylation to allow viral protein synthesis to continue. Deletion of the gene encoding ICP34.5 prevents HSV from replicating in certain cell types, suggesting that eIF2α phosphorylation is critical in restricting infection. PKR is the kinase primarily responsible for the cell-type restriction of ICP34.5-deficient strains. However, if HSV infection also activates PERK, the ESR may partly compensate for PKR loss, and so ICP34.5 might be required to antagonize both PERK and PKR in some contexts. In either case, eIF2α phosphorylation is likely the critical antiviral effect of PERK and PKR activation, because salubrinal, a small-molecule inhibitor of eIF2α dephosphorylation, inhibits HSV replication in wild-type but not eIF2αA/A cells. In the future, it will be important to ask how the deletion of such ESR components as IRE1, XBP-1, PERK, CHOP, and caspase-12 affects the progression of viral infection in cell culture and animal models.

7. CONCLUSION

In a typical yeast cell, more than 1,500 newly synthesized polypeptides enter the ER per second. By extension, in mammalian cells specialized for protein secretion, such as plasma B cells or pancreatic β-islet cells, the flood into the ER is torrential. Because of this centrality of the ER to cell homeostasis, a thorough understanding of the ESR is important for any systems-level model of cell or organismal biology. Indeed, an emerging theme of the recent research in the field is that normal levels of protein flux into the ER can trigger the ESR, and so ESR components are critical for maintaining cell and organ homeostasis, even in the absence of any unusual stress. In addition, because metazoan cells can apoptose in response to ER stress, and because ER dysfunction and ER stress-induced apoptosis are implicated in many important human pathologies, an improved understanding of the ESR may facilitate the development of methods to manipulate these pathways for therapeutic benefit. Therefore, continuing research on ESR pathways promises to yield important basic and clinical insights far into the future.