Abstract
Recent advances in the understanding of the molecular processes contributing to autophagy have provided insight into the relationship between autophagy and apoptosis. In contrast to the concept of “autophagic cell death,” accumulating evidence suggests that autophagy serves a largely cytoprotective role in physiologically relevant conditions. The cytoprotective function of autophagy is mediated in many circumstances by negative modulation of apoptosis. Apoptotic signaling, in turn, serves to inhibit autophagy. While the mechanisms mediating the complex counter-regulation of apoptosis and autophagy are not yet fully understood, important points of crosstalk include the interactions between Beclin-1 and Bcl-2/Bcl-xL and between FADD and Atg5, caspase- and calpain-mediated cleavage of autophagy-related proteins, and autophagic degradation of caspases. Continued investigation of these and other means of crosstalk between apoptosis and autophagy is necessary to elucidate the mechanisms controlling the balance between survival and death both under normal conditions and in diseases including cancer.
Keywords: autophagy, apoptosis, Beclin-1, lymphocytes
References
- Aita V.M., Liang X.H., Murty V.V., Pincus D.L., Yu W., Cayanis E., Kalachikov S., Gilliam T.C., Levine B. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65. doi: 10.1006/geno.1999.5851. [DOI] [PubMed] [Google Scholar]
- Amaravadi R.K., Yu D., Lum J.J., Bui T., Christophorou M.A., Evan G.I., Thomas-Tikhonenko A., Thompson C.B. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest. 2007;117:326–336. doi: 10.1172/JCI28833. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Anglade P., Vyas S., Javoy-Agid F., Herrero M.T., Michel P.P., Marquez J., Mouatt-Prigent A., Ruberg M., Hirsch E.C., Agid Y. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol. 1997;12:25–31. [PubMed] [Google Scholar]
- Arsov I., Adebayo A., Kucerova-Levisohn M., Haye J., MacNeil M., Papavasiliou F.N., Yue Z., Ortiz B.D. A role for autophagic protein beclin 1 early in lymphocyte development. J Immunol. 2011;186:2201–2209. doi: 10.4049/jimmunol.1002223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bell B.D., Leverrier S., Weist B.M., Newton R.H., Arechiga A.F., Luhrs K.A., Morrissette N.S., Walsh C.M. FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells. Proc Natl Acad Sci U S A. 2008;105:16677–16682. doi: 10.1073/pnas.0808597105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Betin V.M., Lane J.D. Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. J Cell Sci. 2009;122:2554–2566. doi: 10.1242/jcs.046250. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bhojani M.S., Rossú B.D., Rehemtulla A. TRAIL and anti-tumor responses. Cancer Biol Ther. 2003;2:S71–S78. doi: 10.4161/cbt.205. [DOI] [PubMed] [Google Scholar]
- Bialik S., Kimchi A. The death-associated protein kinases: structure, function, and beyond. Annu Rev Biochem. 2006;75:189–210. doi: 10.1146/annurev.biochem.75.103004.142615. [DOI] [PubMed] [Google Scholar]
- Carew J.S., Nawrocki S.T., Kahue C.N., Zhang H., Yang C., Chung L., Houghton J.A., Huang P., Giles F.J., Cleveland J. L. Targeting autophagy augments the anticancer activity of the histone deacetylase inhibitor SAHA to overcome Bcr-Ablmediated drug resistance. Blood. 2007;110:313–322. doi: 10.1182/blood-2006-10-050260. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chang N.C., Nguyen M., Germain M., Shore G.C. Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1. EMBO J. 2010;29:606–618. doi: 10.1038/emboj.2009.369. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cho D.H., Jo Y.K., Hwang J.J., Lee Y.M., Roh S.A., Kim J.C. Caspase-mediated cleavage of ATG6/Beclin-1 links apoptosis to autophagy in HeLa cells. Cancer Lett. 2009;274:95–100. doi: 10.1016/j.canlet.2008.09.004. [DOI] [PubMed] [Google Scholar]
- Ciechomska I.A., Goemans C.G., Tolkovsky A.M. Why doesn’t Beclin 1, a BH3-only protein, suppress the anti-apoptotic function of Bcl-2? Autophagy. 2009;5:880–881. doi: 10.4161/auto.9096. [DOI] [PubMed] [Google Scholar]
- Ciechomska I.A., Goemans G.C., Skepper J.N., Tolkovsky A. M. Bcl-2 complexed with Beclin-1 maintains full antiapoptotic function. Oncogene. 2009;28:2128–2141. doi: 10.1038/onc.2009.60. [DOI] [PubMed] [Google Scholar]
- Debnath J., Baehrecke E.H., Kroemer G. Does autophagy contribute to cell death? Autophagy. 2005;1:66–74. doi: 10.4161/auto.1.2.1738. [DOI] [PubMed] [Google Scholar]
- Feng W., Huang S., Wu H., Zhang M. Molecular basis of Bcl-xL’s target recognition versatility revealed by the structure of Bcl-xL in complex with the BH3 domain of Beclin-1. J Mol Biol. 2007;372:223–235. doi: 10.1016/j.jmb.2007.06.069. [DOI] [PubMed] [Google Scholar]
- French L.E., Tschopp J. The TRAIL to selective tumor death. Nat Med. 1999;5:146–147. doi: 10.1038/5505. [DOI] [PubMed] [Google Scholar]
- Furuya N., Yu J., Byfield M., Pattingre S., Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46–52. doi: 10.4161/auto.1.1.1542. [DOI] [PubMed] [Google Scholar]
- Han J., Hou W., Goldstein L.A., Lu C., Stolz D.B., Yin X.M., Rabinowich H. Involvement of protective autophagy in TRAIL resistance of apoptosis-defective tumor cells. J Biol Chem. 2008;283:19665–19677. doi: 10.1074/jbc.M710169200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Han W., Pan H., Chen Y., Sun J., Wang Y., Li J., Ge W., Feng L., Lin X., Wang X., et al. EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells. PLoS One. 2011;6:e18691. doi: 10.1371/journal.pone.0018691. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Herrero-Martín G., Høyer-Hansen M., García-García C., Fumarola C., Farkas T., López-Rivas A., Jäättelä M. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAILtreated epithelial cells. EMBO J. 2009;28:677–685. doi: 10.1038/emboj.2009.8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hou W., Han J., Lu C., Goldstein L.A., Rabinowich H. Enhancement of tumor-TRAIL susceptibility by modulation of autophagy. Autophagy. 2008;4:940–943. doi: 10.4161/auto.6769. [DOI] [PubMed] [Google Scholar]
- Hou W., Han J., Lu C., Goldstein L.A., Rabinowich H. Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis. Autophagy. 2010;6:891–900. doi: 10.4161/auto.6.7.13038. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hou Y.C., Chittaranjan S., Barbosa S.G., McCall K., Gorski S. M. Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis. J Cell Biol. 2008;182:1127–1139. doi: 10.1083/jcb.200712091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hou Y.C., Hannigan A.M., Gorski S.M. An executioner caspase regulates autophagy. Autophagy. 2009;5:530–533. doi: 10.4161/auto.5.4.8061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huang S., Sinicrope F.A. Celecoxib-induced apoptosis is enhanced by ABT-737 and by inhibition of autophagy in human colorectal cancer cells. Autophagy. 2010;6:256–269. doi: 10.4161/auto.6.2.11124. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kang R., Livesey K.M., Zeh H.J., Loze M.T., Tang D. HMGB1: a novel Beclin 1-binding protein active in autophagy. Autophagy. 2010;6:1209–1211. doi: 10.4161/auto.6.8.13651. [DOI] [PubMed] [Google Scholar]
- Kihara A., Kabeya Y., Ohsumi Y., Yoshimori T. Beclinphosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep. 2001;2:330–335. doi: 10.1093/embo-reports/kve061. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kihara A., Noda T., Ishihara N., Ohsumi Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J Cell Biol. 2001;152:519–530. doi: 10.1083/jcb.152.3.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Klionsky D.J. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol. 2007;8:931–937. doi: 10.1038/nrm2245. [DOI] [PubMed] [Google Scholar]
- Kovacs, J.R., Li, C., Yang, Q., Li, G., Garcia, I.G., Ju, S., Roodman, D. G., Windle, J.J., Zhang, X., and Lu, B. (2011). Autophagy promotes T-cell survival through degradation of proteins of the cell death machinery. Cell death and differentiation. 2011 Jun 10. [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
- Kroemer G., Levine B. Autophagic cell death: the story of a misnomer. Nat Rev Mol Cell Biol. 2008;9:1004–1010. doi: 10.1038/nrm2529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee J.S., Li Q., Lee J.Y., Lee S.H., Jeong J.H., Lee H.R., Chang H., Zhou F.C., Gao S.J., Liang C., et al. FLIP-mediated autophagy regulation in cell death control. Nat Cell Biol. 2009;11:1355–1362. doi: 10.1038/ncb1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li D.D., Wang L.L., Deng R., Tang J., Shen Y., Guo J.F., Wang Y., Xia L.P., Feng G.K., Liu Q.Q., et al. The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells. Oncogene. 2009;28:886–898. doi: 10.1038/onc.2008.441. [DOI] [PubMed] [Google Scholar]
- Li H., Wang P., Sun Q., Ding W.X., Yin X.M., Sobol R.W., Stolz D. B., Yu J., Zhang L. Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1. Cancer Res. 2011;71:3625–3634. doi: 10.1158/0008-5472.CAN-10-4475. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liang X.H., Jackson S., Seaman M., Brown K., Kempkes B., Hibshoosh H., Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–676. doi: 10.1038/45257. [DOI] [PubMed] [Google Scholar]
- Liang X.H., Kleeman L.K., Jiang H.H., Gordon G., Goldman J.E., Berry G., Herman B., Levine B. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–8596. doi: 10.1128/jvi.72.11.8586-8596.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu Y., Schiff M., Czymmek K., Tallóczy Z., Levine B., Dinesh-Kumar S.P. Autophagy regulates programmed cell death during the plant innate immune response. Cell. 2005;121:567–577. doi: 10.1016/j.cell.2005.03.007. [DOI] [PubMed] [Google Scholar]
- Luo S., Rubinsztein D.C. Atg5 and Bcl-2 provide novel insights into the interplay between apoptosis and autophagy. Cell Death Differ. 2007;14:1247–1250. doi: 10.1038/sj.cdd.4402149. [DOI] [PubMed] [Google Scholar]
- Luo S., Rubinsztein D.C. Apoptosis blocks Beclin 1-dependent autophagosome synthesis: an effect rescued by Bcl-xL. Cell Death Differ. 2010;17:268–277. doi: 10.1038/cdd.2009.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maiuri M.C., Le Toumelin G., Criollo A., Rain J.C., Gautier F., Juin P., Tasdemir E., Pierron G., Troulinaki K., Tavernarakis N., et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J. 2007;26:2527–2539. doi: 10.1038/sj.emboj.7601689. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Martin D.N., Baehrecke E.H. Caspases function in autophagic programmed cell death in Drosophila. Development. 2004;131:275–284. doi: 10.1242/dev.00933. [DOI] [PubMed] [Google Scholar]
- Matsuura A., Tsukada M., Wada Y., Ohsumi Y. Apg1p, a novel protein kinase required for the autophagic process in Saccharomyces cerevisiae. Gene. 1997;192:245–250. doi: 10.1016/S0378-1119(97)00084-X. [DOI] [PubMed] [Google Scholar]
- McLeod I.X., Zhou X., Li Q.J., Wang F., He Y.W. The Class III Kinase Vps34 Promotes T Lymphocyte Survival through Regulating IL-7Rα Surface Expression. J Immunol. 2011;187:5051–5061. doi: 10.4049/jimmunol.1100710. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Meléndez A., Tallóczy Z., Seaman M., Eskelinen E.L., Hall D.H., Levine B. Autophagy genes are essential for dauer development and life-span extension in C. elegans. Science. 2003;301:1387–1391. doi: 10.1126/science.1087782. [DOI] [PubMed] [Google Scholar]
- Norman J.M., Cohen G.M., Bampton E.T. The in vitro cleavage of the hAtg proteins by cell death proteases. Autophagy. 2010;6:1042–1056. doi: 10.4161/auto.6.8.13337. [DOI] [PubMed] [Google Scholar]
- Oberstein A., Jeffrey P.D., Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282:13123–13132. doi: 10.1074/jbc.M700492200. [DOI] [PubMed] [Google Scholar]
- Ogata M., Hino S., Saito A., Morikawa K., Kondo S., Kanemoto S., Murakami T., Taniguchi M., Tanii I., Yoshinaga K., et al. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol. 2006;26:9220–9231. doi: 10.1128/MCB.01453-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Otto G.P., Wu M.Y., Kazgan N., Anderson O.R., Kessin R.H. Dictyostelium macroautophagy mutants vary in the severity of their developmental defects. J Biol Chem. 2004;279:15621–15629. doi: 10.1074/jbc.M311139200. [DOI] [PubMed] [Google Scholar]
- Pattingre S., Tassa A., Qu X., Garuti R., Liang X.H., Mizushima N., Packer M., Schneider M.D., Levine B. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927–939. doi: 10.1016/j.cell.2005.07.002. [DOI] [PubMed] [Google Scholar]
- Pua H.H., Dzhagalov I., Chuck M., Mizushima N., He Y.W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med. 2007;204:25–31. doi: 10.1084/jem.20061303. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pyo J.O., Jang M.H., Kwon Y.K., Lee H.J., Jun J.I., Woo H.N., Cho D.H., Choi B., Lee H., Kim J.H., et al. Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death. J Biol Chem. 2005;280:20722–20729. doi: 10.1074/jbc.M413934200. [DOI] [PubMed] [Google Scholar]
- Rohn T.T., Wirawan E., Brown R.J., Harris J.R., Masliah E., Vandenabeele P. Depletion of Beclin-1 due to proteolytic cleavage by caspases in the Alzheimer’s disease brain. Neurobiol Dis. 2011;43:68–78. doi: 10.1016/j.nbd.2010.11.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang D., Kang R., Livesey K.M., Cheh C.W., Farkas A., Loughran P., Hoppe G., Bianchi M.E., Tracey K.J., Zeh H.J., 3rd, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol. 2010;190:881–892. doi: 10.1083/jcb.200911078. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Thome M., Tschopp J. Regulation of lymphocyte proliferation and death by FLIP. Nat Rev Immunol. 2001;1:50–58. doi: 10.1038/35095508. [DOI] [PubMed] [Google Scholar]
- Thorburn J., Moore F., Rao A., Barclay W.W., Thomas L.R., Grant K.W., Cramer S.D., Thorburn A. Selective inactivation of a Fas-associated death domain protein (FADD)-dependent apoptosis and autophagy pathway in immortal epithelial cells. Mol Biol Cell. 2005;16:1189–1199. doi: 10.1091/mbc.E04-10-0906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsukada M., Ohsumi Y. Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae. FEBS Lett. 1993;333:169–174. doi: 10.1016/0014-5793(93)80398-E. [DOI] [PubMed] [Google Scholar]
- Walczak H., Miller R.E., Ariail K., Gliniak B., Griffith T.S., Kubin M., Chin W., Jones J., Woodward A., Le T., et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med. 1999;5:157–163. doi: 10.1038/5517. [DOI] [PubMed] [Google Scholar]
- Wang K., Liu R., Li J., Mao J., Lei Y., Wu J., Zeng J., Zhang T., Wu H., Chen L., et al. Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1α-mediated signaling. Autophagy. 2011;7:966–978. doi: 10.4161/auto.7.9.15863. [DOI] [PubMed] [Google Scholar]
- Wei Y., Pattingre S., Sinha S., Bassik M., Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvationinduced autophagy. Mol Cell. 2008;30:678–688. doi: 10.1016/j.molcel.2008.06.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson N.S., Dixit V., Ashkenazi A. Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat Immunol. 2009;10:348–355. doi: 10.1038/ni.1714. [DOI] [PubMed] [Google Scholar]
- Wirawan E., Vande Walle L., Kersse K., Cornelis S., Claerhout S., Vanoverberghe I., Roelandt R., De Rycke R., Verspurten J., Declercq W., et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell death & disease. 2010;1:e18. doi: 10.1038/cddis.2009.16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu H., Wang M.C., Bohmann D. JNK protects Drosophila from oxidative stress by trancriptionally activating autophagy. Mech Dev. 2009;126:624–637. doi: 10.1016/j.mod.2009.06.1082. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yang Z., Klionsky D.J. Eaten alive: a history of macroautophagy. Nat Cell Biol. 2010;12:814–822. doi: 10.1038/ncb0910-814. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Youle R.J., Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 2008;9:47–59. doi: 10.1038/nrm2308. [DOI] [PubMed] [Google Scholar]
- Yousefi S., Perozzo R., Schmid I., Ziemiecki A., Schaffner T., Scapozza L., Brunner T., Simon H.U. Calpainmediated cleavage of Atg5 switches autophagy to apoptosis. Nat Cell Biol. 2006;8:1124–1132. doi: 10.1038/ncb1482. [DOI] [PubMed] [Google Scholar]
- Yu L., Alva A., Su H., Dutt P., Freundt E., Welsh S., Baehrecke E. H., Lenardo M.J. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science. 2004;304:1500–1502. doi: 10.1126/science.1096645. [DOI] [PubMed] [Google Scholar]
- Zalckvar E., Berissi H., Eisenstein M., Kimchi A. Phosphorylation of Beclin 1 by DAP-kinase promotes autophagy by weakening its interactions with Bcl-2 and Bcl-XL. Autophagy. 2009;5:720–722. doi: 10.4161/auto.5.5.8625. [DOI] [PubMed] [Google Scholar]
- Zalckvar E., Berissi H., Mizrachy L., Idelchuk Y., Koren I., Eisenstein M., Sabanay H., Pinkas-Kramarski R., Kimchi A. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 2009;10:285–292. doi: 10.1038/embor.2008.246. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang N., Hartig H., Dzhagalov I., Draper D., He Y.W. The role of apoptosis in the development and function of T lymphocytes. Cell Res. 2005;15:749–769. doi: 10.1038/sj.cr.7290345. [DOI] [PubMed] [Google Scholar]
- Zhang Y., Wu Y., Cheng Y., Zhao Z., Tashiro S., Onodera S., Ikejima T. Fas-mediated autophagy requires JNK activation in HeLa cells. Biochem Biophys Res Commun. 2008;377:1205–1210. doi: 10.1016/j.bbrc.2008.10.151. [DOI] [PubMed] [Google Scholar]
- Zhu Y., Zhao L., Liu L., Gao P., Tian W., Wang X., Jin H., Xu H., Chen Q. Beclin 1 cleavage by caspase-3 inactivates autophagy and promotes apoptosis. Protein cell. 2010;1:468–477. doi: 10.1007/s13238-010-0048-4. [DOI] [PMC free article] [PubMed] [Google Scholar]