This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, D. Y.
Right arrow Articles by Sugden, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, D. Y.
Right arrow Articles by Sugden, B.

 Previous Article  |  Next Article 

Journal of Virology, February 2009, p. 1168-1172, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01358-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MINIREVIEW

The Unfolded Protein Response and Autophagy: Herpesviruses Rule!{triangledown}

Dong Yun Lee,{dagger} Jisook Lee, and Bill Sugden*

McArdle Laboratory for Cancer Research, University of Wisconsin—Madison, Madison, Wisconsin 53706


arrow
INTRODUCTION
 
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 influenza 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{alpha}), 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-box-binding 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 p58^IPK, an inhibitor of PERK (19, 36). Termination of PERK signaling and dephosphorylation of eIF2{alpha} 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 PERK, a kinase central to the UPR, is required for a malfolded protein modeled on those of polyglutamine diseases to induce autophagy (16). In addition, treatment of cells to block posttranslational modifications of proteins can induce both the UPR and autophagy. The formation of autophagosomes under these conditions is inhibited in mouse embryo fibroblasts (MEFs) with deletions of IRE-1, a mediator of one arm of the UPR, indicating that this facet of the UPR is required for autophagy (27, 37). How do herpesviruses cope with these cellular responses and their mechanistic linkage?


arrow
HSV-1
 
During the productive stage of an infection, viral protein synthesis may push the ER's folding capacity to its upper limit. It would not be surprising to observe the activation of UPR under these conditions. However, both PERK and IRE-1 remain inactive in herpes simplex virus type 1 (HSV-1)-infected cells (25). Glycoprotein B (gB) of HSV-1 appears to manipulate PERK by binding to it and leading neither to the phosphorylation of eIF2{alpha} nor to the activation of PERK itself but conferring control on the levels of accumulation of multiple viral proteins in the infected cell (25) (Fig. 1). This blocking of the activation of PERK by gB extends to infected cells in which the UPR is experimentally induced. However, IRE-1 is still activated by this experimental induction of the UPR, indicating that HSV-1 selectively modifies the UPR to its own ends (25). HSV-1 devotes at least two additional genes to regulating the phosphorylation of eIF2{alpha}. As a response to viral infection, the host cell can induce the phosphorylation of eIF2{alpha} by activating PKR. The ICP34.5 gene of HSV-1 encodes a protein that homes the cellular phosphatase protein phosphatase 1 alpha (PP1{alpha}) to eIF2{alpha} to mediate its dephosphorylation (9). The US11 protein of HSV-1 binds PKR to block its phosphorylation of eIF2{alpha} as well (6, 26). HSV-1 blocks phosphorylation of eIF2{alpha}, ensuring support for the efficient synthesis of its own proteins, and subverts PERK to control the accumulation of those proteins. By not activating PERK, HSV-1 gains the additional advantage of not inducing the synthesis of CHOP and its subsequent induction of apoptosis (23, 39).


Figure 1
View larger version (31K):
[in this window]
[in a new window]

  		FIG. 1. During the course of infecting, replicating in, and exiting from a cell, HIV-1 controls the cellular responses of UPR and autophagy. HSV-1 gB inhibits the activation of PERK kinase to block its phosphorylation of eIF2{alpha}. HSV-1's US11 gene product also blocks phosphorylation of eIF2{alpha} by binding the kinase PKR. Finally, the ICP34.5 protein ensures that eIF2{alpha} remains unphosphorylated by bringing the cellular protein PP1{alpha} to it. Phosphorylation of eIF2{alpha} is one consequence of the UPR, which can inhibit protein synthesis and would thus otherwise inhibit viral replication. This inhibition favors HSV-1's replication 1,000-fold. ICP34.5 also inhibits autophagy by binding the Beclin-1 gene, which is required for the induction of this response. It is not yet known if other consequences of the cellular responses, such as the activation of transcription factor ATF6 and spliced XBP-1 by the UPR, are also affected by infection with HSV-1.

HSV-1 uses the same ICP34.5 gene to block autophagy in infected cells (Fig. 1). Infection of MEFs with ICP34.5-null HSV-1 induces autophagy, while infection of PKR-null MEFs with the same virus does not (34). However, ICP34.5 apparently acts not only through eIF2{alpha} to block autophagy but also does so by binding and inhibiting Beclin-1, known too as Atg-6, the first regulator of autophagy identified in mammalian cells (28). Infection with wild-type HSV-1 yields 1,000-fold-more progeny than an ICP34.5-null strain within 3 days of infection of MEFs (35); this advantage appears to be mediated by ICP34.5's blocking the UPR independently of its role in blocking autophagy (1). HSV-1 thus encodes a multifunctional protein to block both the UPR and autophagy to create an environment favorable for its own replication.


arrow
HCMV
 
HCMV also induces the UPR during its productive infection, as evidenced by the accumulation of ATF4, a transcription factor translated when eIF2{alpha} is phosphorylated, and by the accumulation of the spliced form of the XBP-1 message (11). During this infection, ATF6 is not found to be cleaved, indicating that this herpesvirus, too, controls the UPR (11). HCMV infection stimulates the accumulation of BiP; treating cells shortly after infection with a toxin that cleaves BiP blocks the assembly of HCMV particles (5). Stimulation of BiP synthesis is therefore needed to support virus assembly. HCMV uses BiP to its own advantage in a second way. Two viral gene products, US2 and US11, bind BiP to mediate the degradation of major histocompatibility complex class I proteins, thus protecting HCMV's infected host cell from being recognized by a cytotoxic immune response (10). It is not now known if infection with HCMV induces any facets of autophagy. It remains possible that HCMV's fine control of the UPR unlinks these two cellular responses.


arrow
EBV
 
It is clear, however, that Epstein-Barr virus (EBV) regulates both the UPR and autophagy to foster the latent phase of its life cycle. The latent membrane protein 1 (LMP-1) oncogene of EBV induces the UPR dose dependently (21) (Fig. 2). LMP-1 mimics the cellular CD40 receptor and activates NF-{kappa}B, AP1, and the Jak/Stat pathways through it carboxy-terminal signaling domain to promote cell proliferation (4, 14). It uses its amino-terminal, six-membrane-spanning domain to regulate its signaling in lieu of a ligand, and it is this latter domain that induces the UPR, activating PERK, ATF6, and IRE-1 (21). Different cells within clonal populations of EBV-transformed B cells express levels of LMP-1 that range over 100-fold, and those with the highest levels have phosphorylated eIF2{alpha} and decreased levels of protein synthesis and are inhibited in their proliferation (13, 18, 32). LMP-1's dose-dependent activation of PERK stimulates the translation of ATF4 dose-dependently, which drives transcription from LMP-1's promoter and contributes to the accumulation of the LMP-1 protein (21). Given that the prolonged activation of PERK in cells can lead to apoptosis (23, 39), how do EBV-infected cells tolerate its increasing activation? LMP-1 also activates autophagy dose dependently through its last four membrane-spanning domains (20) (Fig. 2). Neither naïve B cells nor their protein A-stimulated blasts show signs of autophagy, which indicates that LMP-1's induction of cell proliferation alone does not induce autophagy (20). EBV-infected B cells that support the most-advanced stages of autophagy also have the highest levels of activated PERK, and in these cells, LMP-1 is degraded rapidly (20). The rapid degradation observed in these cells is inhibited when the cells are treated with lysosome inhibitors, indicating that LMP-1 is likely degraded in these cells by autophagy (J. Lee and B. Sugden, unpublished data). This finding is also supported by studies in which autophagy is inhibited in EBV-transformed B cells. Inhibiting the expression of Beclin-1 with short hairpin RNA, for example, leads to supraphysiological levels of LMP-1 and inhibits the proliferation and/or survival of these cells (20). EBV thus controls both the UPR and autophagy to regulate the levels of its LMP-1 oncogene so that this ligand-independent mimic of a cellular growth receptor signals in a cell autonomous manner.


Figure 2
View larger version (26K):
[in this window]
[in a new window]

  		FIG. 2. EBV infects B lymphocytes and induces and maintains their proliferation while expressing only a small subset of viral genes. One of these, LMP-1, is essential for driving their proliferation. It is expressed at widely different levels in individual cells within clonal populations of infected cells. These levels of expression are controlled by LMP-1's regulation of the UPR and autophagy. LMP-1 activates PERK, which phosphorylates eIF2{alpha}. This phosphorylation promotes expression of ATF4, which increases transcription of LMP-1's promoter. LMP-1's induction of the UPR leads to IRE-1's splicing of XBP-1, which is required for the secretion of the immunoglobulins observed in EBV-infected B cells. High levels of LMP-1 lead to the inhibition of general protein synthesis associated with the UPR and to the final stages of autophagy. This latter response fosters degradation of the high levels of LMP-1, lowering these levels to reset the cell's physiology such that LMP-1 can again drive proliferation and increase its own expression.

EBV's control of the UPR does lead to the induction of XBP-1's spliced form of RNA, a molecule required for the differentiation of plasma cells and the secretion of immunoglobulins (12, 21, 30). These EBV-infected cells do accordingly secrete immunoglobulins at levels of 1 x 107 to 3 x 107 molecules per cell per hour (21). The virus likely benefits from this induction in an unexpected way. In different studies, XBP-1 has been found to stimulate the transcription of EBV's BZLF1 and BRLF1 genes, activators of its productive cycle (3, 33). By controlling the UPR dose dependently with its range of expression of LMP-1, EBV thus positions a subset of infected cells to support its productive cycle when given further appropriate stimulation.


arrow
CONCLUDING REMARKS
 
HSV-1, HCMV, and EBV regulate the UPR and/or autophagy. We now know that HSV-1 and HCMV benefit from these cellular responses during productive infections, while EBV makes use of them during latent infections and likely during its escape from latency. By having evolved in the midst of these two linked responses, these and other herpesviruses have probably adapted to them to benefit themselves. The UPR and autophagy were studied initially as responses to adverse environmental conditions, but now there is growing appreciation that these pathways also affect normal mammalian development and disease. Constituents of the UPR contribute to plasma cell development (30), while their activation is linked to type 2 diabetes (29). Autophagy is required to limit neurodegeneration (7, 15). Herpesviruses infect the differentiated cell types in which the UPR and autophagy contribute to normal function: EBV infects B cells, and HSV-1 infects neurons. Additional studies with herpesviruses should help reveal how the UPR and autophagy contribute to their host cell's life or death in both normal and diseased states.


arrow
ACKNOWLEDGMENTS
 
This work was supported by NIH grants CA070723 and CA022443. Bill Sugden was supported in part while writing this review by a visiting professorship from the University of Hokkaido, Institute for Genetic Medicine, under the auspices of Professor Kenzo Takada. Bill Sugden is an American Cancer Society Research Professor.


arrow
FOOTNOTES
 
* Corresponding author. Mailing address: McArdle Laboratory for Cancer Research, University of Wisconsin School of Medicine and Public Health, 1400 University Ave., Madison, WI 53706. Phone: (608) 262-6697. Fax: (608) 262-2824. E-mail: sugden{at}oncology.wisc.edu Back

{triangledown} Published ahead of print on 10 September 2008. Back

{dagger} Present address: Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0726. Back


arrow
REFERENCES
 
    1
  1. Alexander, D. E., S. L. Ward, N. Mizushima, B. Levine, and D. A. Leib. 2007. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture. J. Virol. 81:12128-12134.[Abstract/Free Full Text]
    2. 2
  2. Bernales, S., K. L. McDonald, and P. Walter. 2006. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol. 4:e423.[CrossRef][Medline]
    3. 3
  3. Bhende, P. M., S. J. Dickerson, X. Sun, W. H. Feng, and S. C. Kenney. 2007. X-box-binding protein 1 activates lytic Epstein-Barr virus gene expression in combination with protein kinase D. J. Virol. 81:7363-7370.[Abstract/Free Full Text]
    4. 4
  4. Brinkmann, M. M., and T. F. Schulz. 2006. Regulation of intracellular signalling by the terminal membrane proteins of members of the Gammaherpesvirinae. J. Gen. Virol. 87:1047-1074.[Abstract/Free Full Text]
    5. 5
  5. Buchkovich, N. J., T. G. Maguire, Y. Yu, A. W. Paton, J. C. Paton, and J. C. Alwine. 2008. Human cytomegalovirus specifically controls the levels of the endoplasmic reticulum chaperone BiP/GRP78, which is required for virion assembly. J. Virol. 82:31-39.[Abstract/Free Full Text]
    6. 6
  6. Cassady, K. A., M. Gross, and B. Roizman. 1998. The herpes simplex virus US11 protein effectively compensates for the {gamma}134.5 gene if present before activation of protein kinase R by precluding its phosphorylation and that of the {alpha} subunit of eukaryotic translation initiation factor 2. J. Virol. 72:8620-8626.[Abstract/Free Full Text]
    7. 7
  7. Hara, T., K. Nakamura, M. Matsui, A. Yamamoto, Y. Nakahara, R. Suzuki-Migishima, M. Yokoyama, K. Mishima, I. Saito, H. Okano, and N. Mizushima. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885-889.[CrossRef][Medline]
    8. 8
  8. Haze, K., H. Yoshida, H. Yanagi, T. Yura, and K. Mori. 1999. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10:3787-3799.[Abstract/Free Full Text]
    9. 9
  9. He, B., J. Chou, D. A. Liebermann, B. Hoffman, and B. Roizman. 1996. The carboxyl terminus of the murine MyD116 gene substitutes for the corresponding domain of the {gamma}134.5 gene of herpes simplex virus to preclude the premature shutoff of total protein synthesis in infected human cells. J. Virol. 70:84-90.[Abstract]
    10. 10
  10. Hegde, N. R., M. S. Chevalier, T. W. Wisner, M. C. Denton, K. Shire, L. Frappier, and D. C. Johnson. 2006. The role of BiP in endoplasmic reticulum-associated degradation of major histocompatibility complex class I heavy chain induced by cytomegalovirus proteins. J. Biol. Chem. 281:20910-20919.[Abstract/Free Full Text]
    11. 11
  11. Isler, J. A., A. H. Skalet, and J. C. Alwine. 2005. Human cytomegalovirus infection activates and regulates the unfolded protein response. J. Virol. 79:6890-6899.[Abstract/Free Full Text]
    12. 12
  12. Iwakoshi, N. N., A. H. Lee, P. Vallabhajosyula, K. L. Otipoby, K. Rajewsky, and L. H. Glimcher. 2003. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4:321-329.[CrossRef][Medline]
    13. 13
  13. Kaykas, A., and B. Sugden. 2000. The amino-terminus and membrane-spanning domains of LMP-1 inhibit cell proliferation. Oncogene 19:1400-1410.[CrossRef][Medline]
    14. 14
  14. Kilger, E., A. Kieser, M. Baumann, and W. Hammerschmidt. 1998. Epstein-Barr virus-mediated B-cell proliferation is dependent upon latent membrane protein 1, which simulates an activated CD40 receptor. EMBO J. 17:1700-1709.[CrossRef][Medline]
    15. 15
  15. Komatsu, M., S. Waguri, T. Chiba, S. Murata, J. Iwata, I. Tanida, T. Ueno, M. Koike, Y. Uchiyama, E. Kominami, and K. Tanaka. 2006. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441:880-884.[CrossRef][Medline]
    16. 16
  16. Kouroku, Y., E. Fujita, I. Tanida, T. Ueno, A. Isoai, H. Kumagai, S. Ogawa, R. J. Kaufman, E. Kominami, and T. Momoi. 2007. ER stress (PERK/eIF2{alpha} phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 14:230-239.[CrossRef][Medline]
    17. 17
  17. Kozutsumi, Y., M. Segal, K. Normington, M. J. Gething, and J. Sambrook. 1988. The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332:462-464.[CrossRef][Medline]
    18. 18
  18. Lam, N., M. L. Sandberg, and B. Sugden. 2004. High physiological levels of LMP1 result in phosphorylation of eIF2{alpha} in Epstein-Barr virus-infected cells. J. Virol. 78:1657-1664.[Abstract/Free Full Text]
    19. 19
  19. Lee, A. H., N. N. Iwakoshi, and L. H. Glimcher. 2003. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23:7448-7459.[Abstract/Free Full Text]
    20. 20
  20. Lee, D. Y., and B. Sugden. 2008. The latent membrane protein 1 oncogene modifies B-cell physiology by regulating autophagy. Oncogene 27:2833-2842.[CrossRef][Medline]
    21. 21
  21. Lee, D. Y., and B. Sugden. 2008. The LMP1 oncogene of EBV activates PERK and the unfolded protein response to drive its own synthesis. Blood 111:2280-2289.[Abstract/Free Full Text]
    22. 22
  22. Levine, B., and G. Kroemer. 2008. Autophagy in the pathogenesis of disease. Cell 132:27-42.[CrossRef][Medline]
    23. 23
  23. Lin, J. H., H. Li, D. Yasumura, H. R. Cohen, C. Zhang, B. Panning, K. M. Shokat, M. M. Lavail, and P. Walter. 2007. IRE1 signaling affects cell fate during the unfolded protein response. Science 318:944-949.[Abstract/Free Full Text]
    24. 24
  24. Meijer, W. H., I. J. van der Klei, M. Veenhuis, and J. A. Kiel. 2007. ATG genes involved in non-selective autophagy are conserved from yeast to man, but the selective Cvt and pexophagy pathways also require organism-specific genes. Autophagy 3:106-116.[Medline]
    25. 25
  25. Mulvey, M., C. Arias, and I. Mohr. 2007. Maintenance of endoplasmic reticulum (ER) homeostasis in herpes simplex virus type 1-infected cells through the association of a viral glycoprotein with PERK, a cellular ER stress sensor. J. Virol. 81:3377-3390.[Abstract/Free Full Text]
    26. 26
  26. Mulvey, M., J. Poppers, D. Sternberg, and I. Mohr. 2003. Regulation of eIF2{alpha} phosphorylation by different functions that act during discrete phases in the herpes simplex virus type 1 life cycle. J. Virol. 77:10917-10928.[Abstract/Free Full Text]
    27. 27
  27. Ogata, M., S. Hino, A. Saito, K. Morikawa, S. Kondo, S. Kanemoto, T. Murakami, M. Taniguchi, I. Tanii, K. Yoshinaga, S. Shiosaka, J. A. Hammarback, F. Urano, and K. Imaizumi. 2006. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26:9220-9231.[Abstract/Free Full Text]
    28. 28
  28. Orvedahl, A., D. Alexander, Z. Talloczy, Q. Sun, Y. Wei, W. Zhang, D. Burns, D. A. Leib, and B. Levine. 2007. HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 1:23-35.[Medline]
    29. 29
  29. Ozcan, U., E. Yilmaz, L. Ozcan, M. Furuhashi, E. Vaillancourt, R. O. Smith, C. Z. Gorgun, and G. S. Hotamisligil. 2006. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313:1137-1140.[Abstract/Free Full Text]
    30. 30
  30. Reimold, A. M., N. N. Iwakoshi, J. Manis, P. Vallabhajosyula, E. Szomolanyi-Tsuda, E. M. Gravallese, D. Friend, M. J. Grusby, F. Alt, and L. H. Glimcher. 2001. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412:300-307.[CrossRef][Medline]
    31. 31
  31. Ron, D. 2002. Proteotoxicity in the endoplasmic reticulum: lessons from the Akita diabetic mouse. J. Clin. Investig. 109:443-445.[CrossRef][Medline]
    32. 32
  32. Sandberg, M. L., A. Kaykas, and B. Sugden. 2000. Latent membrane protein 1 of Epstein-Barr virus inhibits as well as stimulates gene expression. J. Virol. 74:9755-9761.[Abstract/Free Full Text]
    33. 33
  33. Sun, C. C., and D. A. Thorley-Lawson. 2007. Plasma cell-specific transcription factor XBP-1s binds to and transactivates the Epstein-Barr virus BZLF1 promoter. J. Virol. 81:13566-13577.[Abstract/Free Full Text]
    34. 34
  34. Tallóczy, Z., W. Jiang, H. W. Virgin IV, D. A. Leib, D. Scheuner, R. J. Kaufman, E. L. Eskelinen, and B. Levine. 2002. Regulation of starvation- and virus-induced autophagy by the eIF2{alpha} kinase signaling pathway. Proc. Natl. Acad. Sci. USA 99:190-195.[Abstract/Free Full Text]
    35. 35
  35. Tallóczy, Z., H. W. Virgin IV, and B. Levine. 2006. PKR-dependent autophagic degradation of herpes simplex virus type 1. Autophagy 2:24-29.[Medline]
    36. 36
  36. Yan, W., C. L. Frank, M. J. Korth, B. L. Sopher, I. Novoa, D. Ron, and M. G. Katze. 2002. Control of PERK eIF2{alpha} kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc. Natl. Acad. Sci. USA 99:15920-15925.[Abstract/Free Full Text]
    37. 37
  37. Yorimitsu, T., and D. J. Klionsky. 2007. Eating the endoplasmic reticulum: quality control by autophagy. Trends Cell Biol. 17:279-285.[CrossRef][Medline]
    38. 38
  38. Yorimitsu, T., U. Nair, Z. Yang, and D. J. Klionsky. 2006. Endoplasmic reticulum stress triggers autophagy. J. Biol. Chem. 281:30299-30304.[Abstract/Free Full Text]
    39. 39
  39. Zinszner, H., M. Kuroda, X. Wang, N. Batchvarova, R. T. Lightfoot, H. Remotti, J. L. Stevens, and D. Ron. 1998. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12:982-995.[Abstract/Free Full Text]

Journal of Virology, February 2009, p. 1168-1172, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01358-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Lee, D. Y.
Right arrow Articles by Sugden, B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lee, D. Y.
Right arrow Articles by Sugden, B.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»