DOI QR코드

DOI QR Code

A Structural View of Xenophagy, a Battle between Host and Microbes

  • Received : 2017.10.25
  • Accepted : 2017.11.10
  • Published : 2018.01.31

Abstract

The cytoplasm in mammalian cells is a battlefield between the host and invading microbes. Both the living organisms have evolved unique strategies for their survival. The host utilizes a specialized autophagy system, xenophagy, for the clearance of invading pathogens, whereas bacteria secrete proteins to defend and escape from the host xenophagy. Several molecules have been identified and their structural investigation has enabled the comprehension of these mechanisms at the molecular level. In this review, we focus on one example of host autophagy and the other of bacterial defense: the autophagy receptor, NDP52, in conjunction with the sugar receptor, galectin-8, plays a critical role in targeting the autophagy machinery against Salmonella; and the cysteine protease, RavZ secreted by Legionella pneumophila cleaves the LC3-PE on the phagophore membrane. The structure-function relationships of these two examples and the directions of future research will be discussed.

E1BJB7_2018_v41n1_27_f0001.png 이미지

Fig. 1. Overview of xenophagy. Bacteria invade mammalian cells and the carbohydrates originally exposed to the outside the cells arenow towards the inside of the vacuoles (or phagosomes). Bacteria secrete effectors, such as Eis from Mycobacterium tuberculosis, ede-ma factor toxin from Bacillus anthracis, and cholera toxin from Vibrio cholerae, to modulate the induction of the host cell autophagysignaling. Some bacteria escape from the vacuoles and are ubiquitylated by host E3 Ub-ligases, such as LRSAM1, PARKIN, and theLUBAC complex. Most of the bacteria are restricted inside the vacuoles; however, bacterial division ultimately causes the rupture of thephagosomal membrane and, subsequently, the carbohydrates are now exposed to the cytoplasmic space. This acts as a danger signal tothe cells and the carbohydrates are recognized by the sugar receptor GAL8, which immediately recruits the autophagy receptor NDP52.This recognition step by the autophagy system is inhibited by bacterial proteins, such as RavZ from Legionella pneumophila, IcsB fromShigella flexneri, and ActA and internalin K (InlK) from Listeria monocytogenes. RavZ cleaves the LC3-PE molecule, leading to the com-plete inactivation and significant damage to host autophagy. The fusion step between the autophagosome and lysosome for autolyso-somes production is also blocked by VacA from Helicobacter pylori and ESAT-6 (early secreted antigenic target of 6 kDa) from Mycobac-terium tuberculosis. In practice, each xenophagy step is much more detailed and there are many different pathways involved in differentbacteria; these cannot be included in this simplified version.

E1BJB7_2018_v41n1_27_f0002.png 이미지

Fig. 2. Structure-function relationship of the interaction between galectin-8 and NDP52 for clearing invading Salmonella. (A) Domainstructure of NDP52 and the interacting proteins, LC3C, GAL8, and Ub. SKICH (skeletal muscle and kidney-enriched inositol phosphatasecarboxyl homology), CLIR (non-canonical LC3-interaction region), CC (coiled coil), GALBI (galectin-8 binding), and UBZ (ubiquitin-binding zinc finger) domains are colored light brown, orange, green, yellow, and purple, respectively. The interacting LC3C, GAL8, andUb are colored sky blue, salmon, and gray, respectively. (B) The structures of each domain complexed with the interacting partner. Thecolor scheme is the same as for panel (A). The atomic resolution structure of the central CC domain of NDP52 is not available, but thehomodimer forms parallel to CC were revealed by ACCORD and SAXS experiments (Kim et al., 2017). (C) A schematic model for Sal-monella clearance in collaboration between NDP52 and GAL8. The structures and colors for the molecules are the same as panels (A)and (B). The SCV (Salmonella-containing vacuole) is ruptured and the carbohydrates are now exposed to the cytoplasm in mammaliancells. The sugar receptor GAL8 recognizes the carbohydrate by using N-CRD and, simultaneously, the C-CRD of GAL8 binds to theGALBI region of NDP52. The parallel CC dimer of NDP52 is critical for the proper orientation of this bridging molecule. In homodimericNDP52, both GALBI regions point towards SCV and both LIR motifs orient towards LC3-anchored phagophore with proper spacingdefined by the length of CC. Then, the phagophore membrane engulfs the Salmonella to complete the autophagosome.

E1BJB7_2018_v41n1_27_f0003.png 이미지

Fig. 3. Proposed mechanisms of LC3 deconjugation by RavZ from Legionella pneumophila. (A) The domains and overall structure of RavZ.The N- and C-terminal regions containing LIR motifs (N-LIR1/2 colored light brown and C-LIR red) are invisible in electron density map.The catalytic (CAT: residues 49?325) and membrane targeting (MT: residues 326?423) domains are colored blue and orange, respec-tively. (B) The competition between RavZ and cysteine protease ATG4B for the same substrate, LC3B, although the cleavage sites aredifferent. RavZ cleaves the peptide bond between phenylalanine and glycine, whereas ATG4B cleaves the bond between C-terminalglycine and the lipid, phosphatidylethanolamine (PE). (C) The ‘Tethering and Cut’ model. RavZ is targeted to the phagophore membraneand interacts with the LC3-PE molecules anchored in the membrane. By using N- and C-terminal flexible LIR motifs, RavZ is tethered onthe membrane and subsequently cuts the specific peptide bond on the LC3-PE molecule. Currently, it is unclear whether RavZ cleavesone of the tethered LC3 molecules or other nearby LC3 molecules. (D) The ‘Lift and Cut’ model. The targeting of RavZ might be thesame as panel (C). The α3-helix (colored pink) of RavZ docks on the membrane and lifts a LC3-PE molecule via conformational change,after which the LC3-PE is cleaved at the active site of the catalytic domain of RavZ.

Acknowledgement

Supported by : National Research Foundation of Korea (NRF), Samsung Science & Technology Foundation

References

  1. Behrends, C., and Fulda, S. (2012). Receptor proteins in selective autophagy. Int. J. Cell Biol. 2012, 673290.
  2. Boyle, K.B., and Randow, F. (2013). The role of 'eat-me' signals and autophagy cargo receptors in innate immunity. Curr. Opin. Microbiol. 16, 339-348. https://doi.org/10.1016/j.mib.2013.03.010
  3. Celli, J. (2012). LRSAM1, an E3 Ubiquitin ligase with a sense for bacteria. Cell Host. Microbe 12, 735-736. https://doi.org/10.1016/j.chom.2012.11.007
  4. Chen, W., Biswas, T., Porter, V.R., Tsodikov, O.V., and Garneau-Tsodikova, S. (2011). Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB. Proc. Natl. Acad. Sci. USA 108, 9804-9808. https://doi.org/10.1073/pnas.1105379108
  5. Choy, A., Dancourt, J., Mugo, B., O'Connor, T.J., Isberg, R.R., Melia, T.J., and Roy, C.R. (2012). The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 338, 1072-1076. https://doi.org/10.1126/science.1227026
  6. Davis, J., Wang, J., Tropea, J.E., Zhang, D., Dauter, Z., Waugh, D.S., and Wlodawer, A. (2008). Novel fold of VirA, a type III secretion system effector protein from Shigella flexneri. Protein Sci. 17, 2167-2173. https://doi.org/10.1110/ps.037978.108
  7. Fan, E., O'Neal, C.J., Mitchell, D.D., Robien, M.A., Zhang, Z., Pickens, J.C., Tan, X.J., Korotkov, K., Roach, C., Krumm, B., et al. (2004). Structural biology and structure-based inhibitor design of cholera toxin and heat-labile enterotoxin. Int. J. Med. Microbiol. 294, 217-223. https://doi.org/10.1016/j.ijmm.2004.07.002
  8. Farre, J.C., and Subramani, S. (2016). Mechanistic insights into selective autophagy pathways: lessons from yeast. Nat. Rev. Mol. Cell Biol. 17, 537-552.
  9. Gangwer, K.A., Mushrush, D.J., Stauff, D.L., Spiller, B., McClain, M.S., Cover, T.L., and Lacy, D.B. (2007). Crystal structure of the Helicobacter pylori vacuolating toxin p55 domain. Proc. Natl. Acad. Sci. USA 104, 16293-16298. https://doi.org/10.1073/pnas.0707447104
  10. Germane, K.L., Ohi, R., Goldberg, M.B., and Spiller, B.W. (2008). Structural and functional studies indicate that Shigella VirA is not a protease and does not directly destabilize microtubules. Biochemistry 47, 10241-10243. https://doi.org/10.1021/bi801533k
  11. He, H., Dang, Y., Dai, F., Guo, Z., Wu, J., She, X., Pei, Y., Chen, Y., Ling, W., Wu, C., et al. (2003). Post-translational modifications of three members of the human MAP1LC3 family and detection of a novel type of modification for MAP1LC3B. J. Biol. Chem. 278, 29278-29287. https://doi.org/10.1074/jbc.M303800200
  12. Heckmann, B.L., Boada-Romero, E., Cunha, L.D., Magne, J., and Green, D.R. (2017). LC3-Associated Phagocytosis and Inflammation. J. Mol. Biol. 429, 3561-3576. https://doi.org/10.1016/j.jmb.2017.08.012
  13. Holmner, A., Lebens, M., Teneberg, S., Angstrom, J., Okvist, M., and Krengel, U. (2004). Novel binding site identified in a hybrid between cholera toxin and heat-labile enterotoxin: 1.9 $\AA$ crystal structure reveals the details. Structure 12, 1655-1667. https://doi.org/10.1016/j.str.2004.06.022
  14. Hong, S.B., Kim, B.W., Lee, K.E., Kim, S.W., Jeon, H., Kim, J., and Song, H.K. (2011). Insights into noncanonical E1 enzyme activation from the structure of autophagic E1 Atg7 with Atg8. Nat. Struct. Mol. Biol. 18, 1323-1330. https://doi.org/10.1038/nsmb.2165
  15. Hong, S.B., Kim, B.W., Kim, J.H., and Song, H.K. (2012). Structure of the autophagic E2 enzyme Atg10. Acta Crystallogr. D Biol. Crystallogr. 68, 1409-1417. https://doi.org/10.1107/S0907444912034166
  16. Horenkamp, F.A., Kauffman, K.J., Kohler, L.J., Sherwood, R.K., Krueger, K.P., Shteyn, V., Roy, C.R., Melia, T.J., and Reinisch, K.M. (2015). The Legionella anti-autophagy effector RavZ targets the autophagosome via PI3P- and curvature-sensing motifs. Dev. Cell 34, 569-576. https://doi.org/10.1016/j.devcel.2015.08.010
  17. Huang, J., and Klionsky, D.J. (2007). Autophagy and human disease. Cell Cycle 6, 1837-1849. https://doi.org/10.4161/cc.6.15.4511
  18. Huang, J., and Brumell, J.H. (2014). Bacteria-autophagy interplay: a battle for survival. Nat. Rev. Microbiol. 12, 101-114. https://doi.org/10.1038/nrmicro3160
  19. Huett, A., Heath, R.J., Begun, J., Sassi, S.O., Baxt, L.A., Vyas, J.M., Goldberg, M.B., and Xavier, R.J. (2012). The LRR and RING domain protein LRSAM1 is an E3 ligase crucial for ubiquitin-dependent autophagy of intracellular Salmonella Typhimurium. Cell Host Microbe 12, 778-790. https://doi.org/10.1016/j.chom.2012.10.019
  20. Ji, C.H., and Kwon, Y.T. (2017). Crosstalk and Interplay between the Ubiquitin-Proteasome System and Autophagy. Mol. Cells 40, 441-449.
  21. Kim, J.H., and Song, H.K. (2015). Swapping of interaction partners with ATG5 for autophagosome maturation. BMB Rep. 48, 129-130. https://doi.org/10.5483/BMBRep.2015.48.3.048
  22. Kim, K.H., An, D.R., Song, J., Yoon, J.Y., Kim, H.S., Yoon, H.J., Im, H.N., Kim, J., Kim do, J., Lee, S.J., et al. (2012). Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. Proc. Natl. Acad. Sci. USA 109, 7729-7734. https://doi.org/10.1073/pnas.1120251109
  23. Kim, B.W., Hong, S.B., Kim, J.H., Kwon, D.H., and Song, H.K. (2013). Structural basis for recognition of autophagic receptor NDP52 by the sugar receptor galectin-8. Nat. Commun. 4, 1613. https://doi.org/10.1038/ncomms2606
  24. Kim, K.H., An, D.R., Yoon, H.J., Yang, J.K., and Suh, S.W. (2014). Structure of Mycobacterium smegmatis Eis in complex with paromomycin. Acta Crystallogr. F Struct. Biol. Commun. 70, 1173-1179.
  25. Kim, J.H., Hong, S.B., Lee, J.K., Han, S., Roh, K.H., Lee, K.E., Kim, Y.K., Choi, E.J., and Song, H.K. (2015). Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners. Autophagy 11, 75-87. https://doi.org/10.4161/15548627.2014.984276
  26. Kim, B.-W., Kwon, D.H., and Song, H.K. (2016). Structure biology of selective autophagy receptors. BMB Rep. 49, 73-80. https://doi.org/10.5483/BMBRep.2016.49.2.265
  27. Kim, B.W., Jung, Y.O., Kim, M.K., Kwon, D.H., Park, S.H., Kim, J.H., Kuk, Y.B., Oh, S.J., Kim, L., Kim, B.H., et al. (2017). ACCORD: an assessment tool to determine the orientation of homodimeric coiledcoils. Sci. Rep. 7, 43318. https://doi.org/10.1038/srep43318
  28. Klionsky, D.J., and Schulman, B.A. (2014). Dynamic regulation of macroautophagy by distinctive ubiquitin-like proteins. Nat. Struct. Mol. Biol. 21, 336-345. https://doi.org/10.1038/nsmb.2787
  29. Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C.M., Adams, P.D., Adeli, K., et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1-222. https://doi.org/10.1080/15548627.2015.1100356
  30. Kwon, D.H., Kim, L., Kim, B.W., Kim, J.H., Roh, K.H., Choi, E.J., and Song, H.K. (2017a). A novel conformation of the LC3-interacting region motif revealed by the structure of a complex between LC3B and RavZ. Biochem. Biophys. Res. Commun. 490, 1093-1099. https://doi.org/10.1016/j.bbrc.2017.06.173
  31. Kwon, D.H., Kim, S., Jung, Y.O., Roh, K.H., Kim, L., Kim, B.W., Hong, S.B., Lee, I.Y., Song, J.H., Lee, W.C., et al. (2017b). The 1:2 complex between RavZ and LC3 reveals a mechanism for deconjugation of LC3 on the phagophore membrane. Autophagy 13, 70-81. https://doi.org/10.1080/15548627.2016.1243199
  32. Levine, B. (2005). Eating oneself and uninvited guests: autophagyrelated pathways in cellular defense. Cell 120, 159-162.
  33. Levine, B., and Klionsky, D.J. (2017). Autophagy wins the 2016 Nobel Prize in Physiology or Medicine: Breakthroughs in baker's yeast fuel advances in biomedical research. Proc. Natl. Acad. Sci. USA 114, 201-205. https://doi.org/10.1073/pnas.1619876114
  34. Levine, B., Mizushima, N., and Virgin, H.W. (2011). Autophagy in immunity and inflammation. Nature 469, 323-335. https://doi.org/10.1038/nature09782
  35. Li, S., Wandel, M.P., Li, F., Liu, Z., He, C., Wu, J., Shi, Y., and Randow, F. (2013). Sterical hindrance promotes selectivity of the autophagy cargo receptor NDP52 for the danger receptor galectin-8 in antibacterial autophagy. Sci. Signal. 6, ra9. https://doi.org/10.1126/scisignal.6306er9
  36. Liu, X.M., and Du, L.L. (2015). A selective autophagy pathway takes an unconventional route. Autophagy 11, 2381-2382. https://doi.org/10.1080/15548627.2015.1110669
  37. Liu, L., Sakakibara, K., Chen, Q., and Okamoto, K. (2014). Receptormediated mitophagy in yeast and mammalian systems. Cell Res. 24, 787-795. https://doi.org/10.1038/cr.2014.75
  38. Manzanillo, P.S., Ayres, J.S., Watson, R.O., Collins, A.C., Souza, G., Rae, C.S., Schneider, D.S., Nakamura, K., Shiloh, M.U., and Cox, J.S. (2013). The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501, 512-516. https://doi.org/10.1038/nature12566
  39. Maruyama, T., and Noda, N.N. (2018). Autophagy-regulating protease Atg4: structure, function, regulation and inhibition. J. Antibiot. (Tokyo). 71, 72-78. https://doi.org/10.1038/ja.2017.104
  40. Merritt, E.A., Sarfaty, S., van den Akker, F., L'Hoir, C., Martial, J.A., and Hol, W.G. (1994). Crystal structure of cholera toxin B-pentamer bound to receptor GM1 pentasaccharide. Protein Sci. 3, 166-175.
  41. Mizushima, N. (2011). Autophagy in protein and organelle turnover. Cold Spring Harb. Symp. Quant. Biol. 76, 397-402.
  42. Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii, T., George, M.D., Klionsky, D.J., Ohsumi, M., and Ohsumi, Y. (1998). A protein conjugation system essential for autophagy. Nature 395, 395-398. https://doi.org/10.1038/26506
  43. Nah, J., Yuan, J., and Jung, Y.K. (2015). Autophagy in neurodegenerative diseases: from mechanism to therapeutic approach. Mol. Cells 38, 381-389. https://doi.org/10.14348/molcells.2015.0034
  44. Nakatogawa, H., Suzuki, K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10, 458-467. https://doi.org/10.1038/nrm2708
  45. Neves, D., Job, V., Dortet, L., Cossart, P., and Dessen, A. (2013). Structure of internalin InlK from the human pathogen Listeria monocytogenes. J. Mol. Biol. 425, 4520-4529. https://doi.org/10.1016/j.jmb.2013.08.010
  46. Ng, A., and Xavier, R.J. (2011). Leucine-rich repeat (LRR) proteins: integrators of pattern recognition and signaling in immunity. Autophagy 7, 1082-1084. https://doi.org/10.4161/auto.7.9.16464
  47. Ng, A.C., Eisenberg, J.M., Heath, R.J., Huett, A., Robinson, C.M., Nau, G.J., and Xavier, R.J. (2011). Human leucine-rich repeat proteins: a genome-wide bioinformatic categorization and functional analysis in innate immunity. Proc. Natl. Acad. Sci. USA 108 Suppl 1, 4631-4638. https://doi.org/10.1073/pnas.1000093107
  48. Noad, J., von der Malsburg, A., Pathe, C., Michel, M.A., Komander, D., and Randow, F. (2017). LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-kappaB. Nat. Microbiol. 2, 17063. https://doi.org/10.1038/nmicrobiol.2017.63
  49. Ogawa, M., Yoshimori, T., Suzuki, T., Sagara, H., Mizushima, N., and Sasakawa, C. (2005). Escape of intracellular Shigella from autophagy. Science 307, 727-731. https://doi.org/10.1126/science.1106036
  50. Pantoom, S., Yang, A., and Wu, Y.W. (2017). Lift and cut: Anti-host autophagy mechanism of Legionella pneumophila. Autophagy 13, 1467-1469. https://doi.org/10.1080/15548627.2017.1327943
  51. Perrin, A.J., Jiang, X., Birmingham, C.L., So, N.S., and Brumell, J.H. (2004). Recognition of bacteria in the cytosol of Mammalian cells by the ubiquitin system. Curr. Biol. 14, 806-811. https://doi.org/10.1016/j.cub.2004.04.033
  52. Rahighi, S., and Dikic, I. (2012). Selectivity of the ubiquitin-binding modules. FEBS Lett. 586, 2705-2710. https://doi.org/10.1016/j.febslet.2012.04.053
  53. Renshaw, P.S., Lightbody, K.L., Veverka, V., Muskett, F.W., Kelly, G., Frenkiel, T.A., Gordon, S.V., Hewinson, R.G., Burke, B., Norman, J., et al. (2005). Structure and function of the complex formed by the tuberculosis virulence factors CFP-10 and ESAT-6. EMBO J. 24, 2491-2498. https://doi.org/10.1038/sj.emboj.7600732
  54. Santelli, E., Bankston, L.A., Leppla, S.H., and Liddington, R.C. (2004). Crystal structure of a complex between anthrax toxin and its host cell receptor. Nature 430, 905-908. https://doi.org/10.1038/nature02763
  55. Satoo, K., Noda, N.N., Kumeta, H., Fujioka, Y., Mizushima, N., Ohsumi, Y., and Inagaki, F. (2009). The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 28, 1341-1350. https://doi.org/10.1038/emboj.2009.80
  56. Shen, Y., Guo, Q., Zhukovskaya, N.L., Drum, C.L., Bohm, A., and Tang, W.J. (2004). Structure of anthrax edema factor-calmodulinadenosine 5'-(alpha,beta-methylene)-triphosphate complex reveals an alternative mode of ATP binding to the catalytic site. Biochem. Biophys. Res. Commun. 317, 309-314. https://doi.org/10.1016/j.bbrc.2004.03.046
  57. Shin, D.M., Jeon, B.Y., Lee, H.M., Jin, H.S., Yuk, J.M., Song, C.H., Lee, S.H., Lee, Z.W., Cho, S.N., Kim, J.M., et al. (2010). Mycobacterium tuberculosis eis regulates autophagy, inflammation, and cell death through redox-dependent signaling. PLoS Pathog. 6, e1001230. https://doi.org/10.1371/journal.ppat.1001230
  58. Sorbara, M.T., and Girardin, S.E. (2015). Emerging themes in bacterial autophagy. Curr. Opin. Microbiol. 23, 163-170. https://doi.org/10.1016/j.mib.2014.11.020
  59. Svenning, S., and Johansen, T. (2013). Selective autophagy. Essays Biochem. 55, 79-92. https://doi.org/10.1042/bse0550079
  60. Tattoli, I., Sorbara, M.T., Philpott, D.J., and Girardin, S.E. (2012). Bacterial autophagy: the trigger, the target and the timing. Autophagy 8, 1848-1850. https://doi.org/10.4161/auto.21863
  61. Thurston, T.L., Ryzhakov, G., Bloor, S., von Muhlinen, N., and Randow, F. (2009). The TBK1 adaptor and autophagy receptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 10, 1215-1221. https://doi.org/10.1038/ni.1800
  62. Thurston, T.L., Wandel, M.P., von Muhlinen, N., Foeglein, A., and Randow, F. (2012). Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion. Nature 482, 414-418. https://doi.org/10.1038/nature10744
  63. Wen, X., and Klionsky, D.J. (2016). An overview of macroautophagy in yeast. J. Mol. Biol. 428, 1681-1699. https://doi.org/10.1016/j.jmb.2016.02.021
  64. Yang, A., Pantoom, S., and Wu, Y.W. (2017). Elucidation of the antiautophagy mechanism of the Legionella effector RavZ using semisynthetic LC3 proteins. Elife 6, e23905.
  65. Yoshii, S.R., and Mizushima, N. (2017). Monitoring and Measuring Autophagy. Int. J. Mol. Sci. 18, 1865. https://doi.org/10.3390/ijms18091865
  66. Zaffagnini, G., and Martens, S. (2016). Mechanisms of selective autophagy. J. Mol. Biol. 428, 1714-1724. https://doi.org/10.1016/j.jmb.2016.02.004
  67. Zhang, R.G., Scott, D.L., Westbrook, M.L., Nance, S., Spangler, B.D., Shipley, G.G., and Westbrook, E.M. (1995). The three-dimensional crystal structure of cholera toxin. J. Mol. Biol. 251, 563-573. https://doi.org/10.1006/jmbi.1995.0456

Cited by

  1. Chronic Infections: A Possible Scenario for Autophagy and Senescence Cross-Talk vol.7, pp.10, 2018, https://doi.org/10.3390/cells7100162
  2. Epigenetic Regulation of Autophagy: A Path to the Control of Autoimmunity vol.9, pp.1664-3224, 2018, https://doi.org/10.3389/fimmu.2018.01864
  3. Galectins at a glance vol.131, pp.9, 2018, https://doi.org/10.1242/jcs.208884