The unfolded protein response (UPR) and autophagy are two cellular environmental responses that affect a cell’s life or death. The UPR begins on the sensing of an excess of unfolded proteins in the endoplasmic reticulum (ER). Autophagy, originally discovered as a response to nutrient depletion, is involved in development, in the degradation of cellular components, and in the reaction to intracellular bacteria and viruses. Some herpesviruses now appear to modify one or both of these responses to their own advantages during productive and latent infections. We know that the UPR can be mechanistically linked to autophagy, prompting the notion that herpesviruses may modify both responses by regulating one or that they may even uncouple them. The UPR is induced when the ER responds to an overload of unfolded proteins. For example, malfolded forms of inffuenza virus hemagglutinin induce increased synthesis of the immunoglobulin heavy chain-binding protein, a chaperone termed BiP, which is diagnostic of the UPR (17). When the capacities of BiP and other ER-resident chaperones are surpassed, the UPR is induced, leading eventually to increases in the levels of these chaperones. Three regulatory paths central to the UPR are activated in the ER upon its induction. One involves activating transcription factor 6 (ATF6), which is transported to the Golgi compartment, where it is cleaved and released to translocate to the nucleus and there induce transcription of genes such as the BiP gene (8). The second path uses PKR-like ER kinase (PERK), which, when induced, phosphorylates eukaryotic initiation factor 2 alpha (eIF2), which inhibits general protein synthesis and, along with ATF4, induces expression of the CCAAT/enhancer-binding protein-homologous protein (CHOP)(31). Under some conditions, CHOP can lead to apoptosis in cells undergoing the UPR (39). A third path is mediated by inositol-requiring kinase 1 (IRE-1), which is induced to splice the RNA that encodes X-boxbinding protein 1 (XBP-1) in an enzymatically unconventional process. The spliced XBP-1 message is translated into a transcription factor, which moves to the nucleus to transcribe multiple genes whose products ultimately home to the ER, including p58IPK, an inhibitor of PERK (19, 36). Termination of PERK signaling and dephosphorylation of eIF2 in the later stages of the UPR permit the synthetic phase of the UPR, which requires new protein synthesis. Autophagy is a response dissected genetically in yeast that leads to the envelopment of cytoplasmic organelles and potentially to their degradation. It is characterized by the formation of double-membrane-bound vesicles whose formation is dependent on multiple genes conserved from Saccharomyces cerevisiae to mammals (24). These double-membrane-bound vesicles, termed autophagosomes, can fuse with lysosomes to allow their contents, including whole organelles, to be degraded. The products of this degradation include amino acids that can both be used in protein synthesis and contribute to energy metabolism (22). Thus, when induced by nutrient deprivation, autophagy can lead to the redistribution of synthetic components and the energy needed for the cell to survive. Autophagy is regulated by multiple signals. It is inhibited, for example, by TOR kinase, so growth factors that affect TOR kinase also affect autophagy (22). It is clear that the UPR can induce autophagy in S. cerevisiae such that portions of the ER are contained within and help form its double-membrane vesicles (2, 38). Other evidence supports this mechanistic linkage of the UPR to autophagy in mammalian cells. For example, the activation of …