Discussion:
Autophagy is a regulated cytoprotective cellular response to stress or infection. It should therefore not be surprising that the extracellular system of complement proteins, known to act as pathogen and danger sensors, should be able to induce autophagy as a reactive response within host cells, contributing to pathogen clearance and enhanced cellular survival. This occurs not only by signal transduction via cell-surface receptors (summarized in figure 1 ), such as in the case of CD46, VSIG4, and the anaphylatoxin receptors, but also by direct interaction of C3 with cytosolic proteins, once C3 activation products are carried into the cell on the surface of invading pathogens (Tam et al., 2014)(Sorbara et al., 2018). What is more surprising however is the evidence that C3 also exists within the cytosolic fraction of cells, separate from the secretory pathway (King et al., 2019). In parallel to C3(b) being introduced into the cell on bacterial surfaces and interacting with ATG16L1, inducing xenophagy, we also see evidence that cytosolic C3 is also involved in homeostatic autophagy. Careful regulation of C3 activation is a key feature of the extracellular complement system (Sjoberg, Trouw, & Blom, 2009), and the same should also be true of intracellular, cytosolic C3. The mechanistic details of how autophagy is triggered by intracellular C3 or C3 cleavage products, and how this is regulated, are currently under investigation, but potential interactions are presented in figure 2 . The opsonizing ability of C3 derives from the presence of the thioester group that is exposed after C3 cleavage. We found that native C3 and its thioester-exposed (C3(H2O) and C3-methylamine) but not cleaved products (C3b, iC3b, C3d and C3c) have higher affinity to ATG16L1 (King et al., 2019), providing a possibility for intracellular reaction-driven conformational changes of C3 regulating binding to desired surfaces or ligands, in the same way in which C3 cleavage alters binding affinity to known ligands and receptors in the extracellular environment (Ricklin et al., 2016). The interaction of ATG16L1 with full-length C3 provides a possible mechanism of regulation of interaction, by cleavage of C3. Cytosolic C3 may also be involved in the tethering of cellular components required for progression of autophagosome maturation, thereby regulating ATG16L1 complex recruitment, as it known that proper localization of the ATG16L1 complex is essential for lipidation of LC3-I to LC3-II for phagophore membrane elongation. Maturation of the autophagosome is accompanied by the dissociation of ATG proteins (including ATG16L1), that occurs prior to fusion with lysosomes. Thus, cleavage of C3 may decrease binding affinity to ATG16L1, leading to dissociation of ATG16L1 from autophagosomes, allowing fusion with lysosomes. Alternatively or additionally, C3 fragments remaining on the autophagosome surface might be involved in dynamics of autophagosome and lysosome fusion, by interaction with other factors. Although the scenarios of C3 involvement in autophagy pathway described here are all hypothetical, they are conceivable as based on the current understanding of C3 and diversity of its binding ligands, dependent on the state of C3 processing. Further experimental investigation is required.
The mechanism for the interaction domain of ATG16L1 with C3, or C3 cleavage products, must also be defined. Combining our findings (King et al., 2019) with that of Sorbara et al (Sorbara et al., 2018), we can deduce that C3 interacts with the central coiled coil domain of ATG16L1, the only domain common to both the positive hits on protein microarrays and the positive result found by yeast 2 hybrid assay (figure 3 ). This domain is present in both mammal and yeast ATG16L1/ATG16 and is required for homeostatic autophagy (Rai et al., 2019), and is responsible for ATG16L1 homodimerisation and lipid binding (Dudley et al., 2019), therefore mediating recruitment to the elongating isolation membrane of the forming autophagosome. ATG16L1 is recruited to the forming phagophore by WIPI2, which also binds to the coiled coil domain and is also involved in both homeostatic autophagy and xenophagy (Dooley et al., 2014). It is possible that C3 functions in a similar manner, whereby C3 deposited on intracellular pathogens, or material to be recycled, recruits ATG16L1 which then, in complex with ATG5 and ATG12, lipidates LC3-II and contributes to the growing phagophore. We have identified that the ATG16L1-recruiting amino acid motif found on TMEM59, TLR2 and NOD2 (Boada-Romero et al., 2013) is also present at C31206-1216, within the C3d fragment of C3, and overlapping with the known CR2 binding site. In the extracellular environment, this binding site is only revealed once C3 is cleaved by factor I and undergoes subsequent conformational changes, but this could be the mechanism by which ATG16L1 is recruited to complement opsonised cyto-invasive pathogens. Investigation of these molecular interactions is ongoing.
What is clear however, is that C3-opsonised bacteria are targeted for destruction within eukaryotic cells via autophagy-dependent xenophagy (Sorbara et al., 2018), should they invade cells before destruction by complement-mediated phagocytosis. It remains to be shown directly whether intracellular ‘self’-material can also be marked by intracellular C3 for autophagic clearance, mirroring the extracellular clearance of self-material such as apoptotic cells and immune complexes, and whether familiar features of C3 so important to its extracelluar function, such as the thioester group, are also required for this intracellular function. It should be noted however, that thioester containing proteins (TEPs) are conserved across species, mediating similar functions within innate immunity in insects, tunicates, and mammals (Nonaka, 2014). A conserved connection between TEPs and autophagy can be observed in the finding that the Drosophila TEP and complement orthologue Macroglobulin Complement-Related (MCR) plays an essential role in development and inflammation, by mediating autophagy in macrophages, via an immune cell-surface receptor (Lin et al., 2017). C3 has so many diverse functions, from opsonin, warning signal, phagocytosis inducer, mediator of clearance, and even acting as a component of its own convertase, that it has been termed a “Swiss army knife” of a protein (Ricklin et al., 2016). Given its clearly understood function in the clearance of extracellular material for disposal, it may be unsurprising to find that it has parallel functions within the cell as well. Production of multiple protein variants from one gene is a fundamental process allowing proteome diversity, and generates potential for evolutionary adaptivity, whereby one variant can take on new or non-overlapping functions (Conant & Wolfe, 2008). The discovery of a cytoprotective intracellular function of C3 supports an emerging concept of complement as a defender of the intracellular space (Elvington, Liszewski, & Atkinson, 2016). Now it remains to be seen how far, beyond β-cells, C3-regulated autophagy plays a significant role in determining cell fates.
References:
Bachar-Wikstrom, E., Wikstrom, J. D., Ariav, Y., Tirosh, B., Kaiser, N., Cerasi, E., & Leibowitz, G. (2013). Stimulation of autophagy improves endoplasmic reticulum stress-induced diabetes. Diabetes, 62 (4), 1227-1237. doi:10.2337/db12-1474
Birmingham, C. L., Canadien, V., Gouin, E., Troy, E. B., Yoshimori, T., Cossart, P., . . . Brumell, J. H. (2007). Listeria monocytogenes evades killing by autophagy during colonization of host cells. Autophagy, 3 (5), 442-451. doi:10.4161/auto.4450
Bjorkoy, G., Lamark, T., Brech, A., Outzen, H., Perander, M., Overvatn, A., . . . Johansen, T. (2005). p62/SQSTM1 forms protein aggregates degraded by autophagy and has a protective effect on huntingtin-induced cell death. J Cell Biol, 171 (4), 603-614. doi:10.1083/jcb.200507002
Boada-Romero, E., Letek, M., Fleischer, A., Pallauf, K., Ramon-Barros, C., & Pimentel-Muinos, F. X. (2013). TMEM59 defines a novel ATG16L1-binding motif that promotes local activation of LC3. EMBO J, 32 (4), 566-582. doi:10.1038/emboj.2013.8
Cattaneo, R. (2004). Four viruses, two bacteria, and one receptor: membrane cofactor protein (CD46) as pathogens’ magnet. J Virol, 78 (9), 4385-4388. doi:10.1128/jvi.78.9.4385-4388.2004
Chen, H. D., Kao, C. Y., Liu, B. Y., Huang, S. W., Kuo, C. J., Ruan, J. W., . . . Chen, C. S. (2017). HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. Autophagy, 13 (2), 371-385. doi:10.1080/15548627.2016.1256933
Chiang, H. L., Terlecky, S. R., Plant, C. P., & Dice, J. F. (1989). A role for a 70-kilodalton heat shock protein in lysosomal degradation of intracellular proteins. Science, 246 (4928), 382-385. doi:10.1126/science.2799391
Conant, G. C., & Wolfe, K. H. (2008). Turning a hobby into a job: how duplicated genes find new functions. Nat Rev Genet, 9 (12), 938-950. doi:10.1038/nrg2482
Cravedi, P., Leventhal, J., Lakhani, P., Ward, S. C., Donovan, M. J., & Heeger, P. S. (2013). Immune cell-derived C3a and C5a costimulate human T cell alloimmunity. Am J Transplant, 13 (10), 2530-2539. doi:10.1111/ajt.12405
de Perrot, M., Liu, M., Waddell, T. K., & Keshavjee, S. (2003). Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med, 167 (4), 490-511. doi:10.1164/rccm.200207-670SO
Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C., & Fearon, D. T. (1996). C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science, 271 (5247), 348-350. doi:10.1126/science.271.5247.348
Dice, J. F. (1990). Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem Sci, 15 (8), 305-309. doi:10.1016/0968-0004(90)90019-8
Dikic, I., & Elazar, Z. (2018). Mechanism and medical implications of mammalian autophagy. Nat Rev Mol Cell Biol, 19 (6), 349-364. doi:10.1038/s41580-018-0003-4
Dooley, H. C., Razi, M., Polson, H. E., Girardin, S. E., Wilson, M. I., & Tooze, S. A. (2014). WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell, 55 (2), 238-252. doi:10.1016/j.molcel.2014.05.021
Doorduijn, D. J., Rooijakkers, S. H. M., & Heesterbeek, D. A. C. (2019). How the Membrane Attack Complex Damages the Bacterial Cell Envelope and Kills Gram-Negative Bacteria. Bioessays, 41 (10), e1900074. doi:10.1002/bies.201900074
Dortet, L., Mostowy, S., Samba-Louaka, A., Gouin, E., Nahori, M. A., Wiemer, E. A., . . . Cossart, P. (2011). Recruitment of the major vault protein by InlK: a Listeria monocytogenes strategy to avoid autophagy.PLoS Pathog, 7 (8), e1002168. doi:10.1371/journal.ppat.1002168
Dudley, L. J., Cabodevilla, A. G., Makar, A. N., Sztacho, M., Michelberger, T., Marsh, J. A., . . . Gammoh, N. (2019). Intrinsic lipid binding activity of ATG16L1 supports efficient membrane anchoring and autophagy. EMBO J, 38 (9). doi:10.15252/embj.2018100554
Ebato, C., Uchida, T., Arakawa, M., Komatsu, M., Ueno, T., Komiya, K., . . . Watada, H. (2008). Autophagy is important in islet homeostasis and compensatory increase of beta cell mass in response to high-fat diet.Cell Metab, 8 (4), 325-332. doi:10.1016/j.cmet.2008.08.009
Elvington, M., Liszewski, M. K., & Atkinson, J. P. (2016). Evolution of the complement system: from defense of the single cell to guardian of the intravascular space. Immunol Rev, 274 (1), 9-15. doi:10.1111/imr.12474
Elvington, M., Liszewski, M. K., Bertram, P., Kulkarni, H. S., & Atkinson, J. P. (2017). A C3(H20) recycling pathway is a component of the intracellular complement system. J Clin Invest, 127 (3), 970-981. doi:10.1172/JCI89412
Fletcher, K., Ulferts, R., Jacquin, E., Veith, T., Gammoh, N., Arasteh, J. M., . . . Florey, O. (2018). The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes.EMBO J, 37 (4). doi:10.15252/embj.201797840
Foss, S., Watkinson, R., Sandlie, I., James, L. C., & Andersen, J. T. (2015). TRIM21: a cytosolic Fc receptor with broad antibody isotype specificity. Immunol Rev, 268 (1), 328-339. doi:10.1111/imr.12363
Fujita, N., Itoh, T., Omori, H., Fukuda, M., Noda, T., & Yoshimori, T. (2008). The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell, 19 (5), 2092-2100. doi:10.1091/mbc.E07-12-1257
Gonzalez, S. F., Lukacs-Kornek, V., Kuligowski, M. P., Pitcher, L. A., Degn, S. E., Turley, S. J., & Carroll, M. C. (2010). Complement-dependent transport of antigen into B cell follicles. J Immunol, 185 (5), 2659-2664. doi:10.4049/jimmunol.1000522
Harris, J., Hartman, M., Roche, C., Zeng, S. G., O’Shea, A., Sharp, F. A., . . . Lavelle, E. C. (2011). Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem, 286 (11), 9587-9597. doi:10.1074/jbc.M110.202911
Helmy, K. Y., Katschke, K. J., Jr., Gorgani, N. N., Kljavin, N. M., Elliott, J. M., Diehl, L., . . . van Lookeren Campagne, M. (2006). CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell, 124 (5), 915-927. doi:10.1016/j.cell.2005.12.039
Hohmeier, H. E., Mulder, H., Chen, G., Henkel-Rieger, R., Prentki, M., & Newgard, C. B. (2000). Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes, 49 (3), 424-430.
Hu, R., Chen, Z. F., Yan, J., Li, Q. F., Huang, Y., Xu, H., . . . Jiang, H. (2014). Complement C5a exacerbates acute lung injury induced through autophagy-mediated alveolar macrophage apoptosis. Cell Death Dis, 5 , e1330. doi:10.1038/cddis.2014.274
Ichimura, Y., Kumanomidou, T., Sou, Y. S., Mizushima, T., Ezaki, J., Ueno, T., . . . Komatsu, M. (2008). Structural basis for sorting mechanism of p62 in selective autophagy. J Biol Chem, 283 (33), 22847-22857. doi:10.1074/jbc.M802182200
Ji, J., Petropavlovskaia, M., Khatchadourian, A., Patapas, J., Makhlin, J., Rosenberg, L., & Maysinger, D. (2019). Type 2 diabetes is associated with suppression of autophagy and lipid accumulation in beta-cells. J Cell Mol Med, 23 (4), 2890-2900. doi:10.1111/jcmm.14172
Joubert, P. E., Meiffren, G., Gregoire, I. P., Pontini, G., Richetta, C., Flacher, M., . . . Faure, M. (2009). Autophagy induction by the pathogen receptor CD46. Cell Host Microbe, 6 (4), 354-366. doi:10.1016/j.chom.2009.09.006
Jung, H. S., Chung, K. W., Won Kim, J., Kim, J., Komatsu, M., Tanaka, K., . . . Lee, M. S. (2008). Loss of autophagy diminishes pancreatic beta cell mass and function with resultant hyperglycemia. Cell Metab, 8 (4), 318-324. doi:10.1016/j.cmet.2008.08.013
Jurgens, C. A., Toukatly, M. N., Fligner, C. L., Udayasankar, J., Subramanian, S. L., Zraika, S., . . . Hull, R. L. (2011). beta-cell loss and beta-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol, 178 (6), 2632-2640. doi:S0002-9440(11)00270-7 [pii]10.1016/j.ajpath.2011.02.036
Kabeya, Y., Mizushima, N., Ueno, T., Yamamoto, A., Kirisako, T., Noda, T., . . . Yoshimori, T. (2000). LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing.EMBO J, 19 (21), 5720-5728. doi:10.1093/emboj/19.21.5720
Kaushik, S., & Cuervo, A. M. (2018). The coming of age of chaperone-mediated autophagy. Nat Rev Mol Cell Biol, 19 (6), 365-381. doi:10.1038/s41580-018-0001-6
Kemper, C., Chan, A. C., Green, J. M., Brett, K. A., Murphy, K. M., & Atkinson, J. P. (2003). Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype. Nature, 421 (6921), 388-392. doi:10.1038/nature01315
Keshavjee, S., Davis, R. D., Zamora, M. R., de Perrot, M., & Patterson, G. A. (2005). A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings. J Thorac Cardiovasc Surg, 129 (2), 423-428. doi:10.1016/j.jtcvs.2004.06.048
Kim, K. H., Choi, B. K., Kim, Y. H., Han, C., Oh, H. S., Lee, D. G., & Kwon, B. S. (2016). Extracellular stimulation of VSIG4/complement receptor Ig suppresses intracellular bacterial infection by inducing autophagy. Autophagy, 12 (9), 1647-1659. doi:10.1080/15548627.2016.1196314
Kim, K. H., Choi, B. K., Song, K. M., Cha, K. W., Kim, Y. H., Lee, H., . . . Kwon, B. S. (2013). CRIg signals induce anti-intracellular bacterial phagosome activity in a chloride intracellular channel 3-dependent manner. Eur J Immunol, 43 (3), 667-678. doi:10.1002/eji.201242997
King, B. C., & Blom, A. M. (2017). Non-traditional roles of complement in type 2 diabetes: Metabolism, insulin secretion and homeostasis.Mol Immunol, 84 , 34-42. doi:10.1016/j.molimm.2016.12.009
King, B. C., Esguerra, J. L., Golec, E., Eliasson, L., Kemper, C., & Blom, A. M. (2016). CD46 Activation Regulates miR-150-Mediated Control of GLUT1 Expression and Cytokine Secretion in Human CD4+ T Cells.J Immunol, 196 (4), 1636-1645. doi:10.4049/jimmunol.1500516
King, B. C., Kulak, K., Krus, U., Rosberg, R., Golec, E., Wozniak, K., . . . Blom, A. M. (2019). Complement Component C3 Is Highly Expressed in Human Pancreatic Islets and Prevents beta Cell Death via ATG16L1 Interaction and Autophagy Regulation. Cell Metab, 29 (1), 202-210 e206. doi:10.1016/j.cmet.2018.09.009
Klionsky, D. J., Abdelmohsen, K., Abe, A., Abedin, M. J., Abeliovich, H., Acevedo Arozena, A., . . . Zughaier, S. M. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12 (1), 1-222. doi:10.1080/15548627.2015.1100356
Kloft, N., Neukirch, C., Bobkiewicz, W., Veerachato, G., Busch, T., von Hoven, G., . . . Husmann, M. (2010). Pro-autophagic signal induction by bacterial pore-forming toxins. Med Microbiol Immunol, 199 (4), 299-309. doi:10.1007/s00430-010-0163-0
Koentjoro, B., Park, J. S., & Sue, C. M. (2017). Nix restores mitophagy and mitochondrial function to protect against PINK1/Parkin-related Parkinson’s disease. Sci Rep, 7 , 44373. doi:10.1038/srep44373
Kohl, J. (2006). The role of complement in danger sensing and transmission. Immunol Res, 34 (2), 157-176. doi:IR:34:2:157 [pii]10.1385/IR:34:2:157
Kolev, M., Dimeloe, S., Le Friec, G., Navarini, A., Arbore, G., Povoleri, G. A., . . . Kemper, C. (2015). Complement Regulates Nutrient Influx and Metabolic Reprogramming during Th1 Cell Responses.Immunity, 42 (6), 1033-1047. doi:10.1016/j.immuni.2015.05.024
Kolev, M., & Kemper, C. (2017). Keeping It All Going-Complement Meets Metabolism. Front Immunol, 8 , 1. doi:10.3389/fimmu.2017.00001
Kong, F. J., Wu, J. H., Sun, S. Y., & Zhou, J. Q. (2017). The endoplasmic reticulum stress/autophagy pathway is involved in cholesterol-induced pancreatic beta-cell injury. Sci Rep, 7 , 44746. doi:10.1038/srep44746
Kozak, M. (1978). How do eucaryotic ribosomes select initiation regions in messenger RNA? Cell, 15 (4), 1109-1123. doi:10.1016/0092-8674(78)90039-9
Kremlitzka, M., Nowacka, A. A., Mohlin, F. C., Bompada, P., De Marinis, Y., & Blom, A. M. (2019). Interaction of Serum-Derived and Internalized C3 With DNA in Human B Cells-A Potential Involvement in Regulation of Gene Transcription. Front Immunol, 10 , 493. doi:10.3389/fimmu.2019.00493
Kulkarni, H. S., Elvington, M. L., Perng, Y. C., Liszewski, M. K., Byers, D. E., Farkouh, C., . . . Atkinson, J. P. (2019). Intracellular C3 Protects Human Airway Epithelial Cells from Stress-associated Cell Death. Am J Respir Cell Mol Biol, 60 (2), 144-157. doi:10.1165/rcmb.2017-0405OC
Lambris, J. D., Ricklin, D., & Geisbrecht, B. V. (2008). Complement evasion by human pathogens. Nat Rev Microbiol, 6 (2), 132-142. doi:10.1038/nrmicro1824
Li, W. W., Li, J., & Bao, J. K. (2012). Microautophagy: lesser-known self-eating. Cell Mol Life Sci, 69 (7), 1125-1136. doi:10.1007/s00018-011-0865-5
Lin, L., Rodrigues, F., Kary, C., Contet, A., Logan, M., Baxter, R. H. G., . . . Baehrecke, E. H. (2017). Complement-Related Regulates Autophagy in Neighboring Cells. Cell, 170 (1), 158-171 e158. doi:10.1016/j.cell.2017.06.018
Liszewski, M. K., Post, T. W., & Atkinson, J. P. (1991). Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu Rev Immunol, 9 , 431-455. doi:10.1146/annurev.iy.09.040191.002243
Liu, W. J., Li, Z. H., Chen, X. C., Zhao, X. L., Zhong, Z., Yang, C., . . . Liu, H. F. (2017). Blockage of the lysosome-dependent autophagic pathway contributes to complement membrane attack complex-induced podocyte injury in idiopathic membranous nephropathy. Sci Rep, 7 (1), 8643. doi:10.1038/s41598-017-07889-z
Lv, Q., Yang, F., Chen, K., & Zhang, Y. (2016). Autophagy protects podocytes from sublytic complement induced injury. Exp Cell Res, 341 (2), 132-138. doi:10.1016/j.yexcr.2016.02.009
Ma, H., Sandor, D. G., & Beck, L. H., Jr. (2013). The role of complement in membranous nephropathy. Semin Nephrol, 33 (6), 531-542. doi:10.1016/j.semnephrol.2013.08.004
Mallery, D. L., McEwan, W. A., Bidgood, S. R., Towers, G. J., Johnson, C. M., & James, L. C. (2010). Antibodies mediate intracellular immunity through tripartite motif-containing 21 (TRIM21). Proc Natl Acad Sci U S A, 107 (46), 19985-19990. doi:10.1073/pnas.1014074107
Masini, M., Bugliani, M., Lupi, R., del Guerra, S., Boggi, U., Filipponi, F., . . . Marchetti, P. (2009). Autophagy in human type 2 diabetes pancreatic beta cells. Diabetologia, 52 (6), 1083-1086. doi:10.1007/s00125-009-1347-2
McEwan, W. A., Tam, J. C., Watkinson, R. E., Bidgood, S. R., Mallery, D. L., & James, L. C. (2013). Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol, 14 (4), 327-336. doi:10.1038/ni.2548
Naka, Y., Marsh, H. C., Scesney, S. M., Oz, M. C., & Pinsky, D. J. (1997). Complement activation as a cause for primary graft failure in an isogeneic rat model of hypothermic lung preservation and transplantation. Transplantation, 64 (9), 1248-1255. doi:10.1097/00007890-199711150-00004
Nakagawa, I., Amano, A., Mizushima, N., Yamamoto, A., Yamaguchi, H., Kamimoto, T., . . . Yoshimori, T. (2004). Autophagy defends cells against invading group A Streptococcus. Science, 306 (5698), 1037-1040. doi:10.1126/science.1103966
Nakamura, S., & Yoshimori, T. (2017). New insights into autophagosome-lysosome fusion. J Cell Sci, 130 (7), 1209-1216. doi:10.1242/jcs.196352
Nguyen, H., Kuril, S., Bastian, D., Kim, J., Zhang, M., Vaena, S. G., . . . Yu, X. Z. (2018). Complement C3a and C5a receptors promote GVHD by suppressing mitophagy in recipient dendritic cells. JCI Insight, 3 (24). doi:10.1172/jci.insight.121697
Nguyen, T. N., Padman, B. S., Usher, J., Oorschot, V., Ramm, G., & Lazarou, M. (2016). Atg8 family LC3/GABARAP proteins are crucial for autophagosome-lysosome fusion but not autophagosome formation during PINK1/Parkin mitophagy and starvation. J Cell Biol, 215 (6), 857-874. doi:10.1083/jcb.201607039
Nonaka, M. (2014). Evolution of the complement system. Subcell Biochem, 80 , 31-43. doi:10.1007/978-94-017-8881-6_3
O’Neill, L. A., Kishton, R. J., & Rathmell, J. (2016). A guide to immunometabolism for immunologists. Nat Rev Immunol, 16 (9), 553-565. doi:10.1038/nri.2016.70
Otomo, C., Metlagel, Z., Takaesu, G., & Otomo, T. (2013). Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy. Nat Struct Mol Biol, 20 (1), 59-66. doi:10.1038/nsmb.2431
Pattingre, S., Tassa, A., Qu, X., Garuti, R., Liang, X. H., Mizushima, N., . . . Levine, B. (2005). Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell, 122 (6), 927-939. doi:10.1016/j.cell.2005.07.002
Pierre, A. F., Xavier, A. M., Liu, M., Cassivi, S. D., Lindsay, T. F., Marsh, H. C., . . . Keshavjee, S. H. (1998). Effect of complement inhibition with soluble complement receptor 1 on pig allotransplant lung function. Transplantation, 66 (6), 723-732. doi:10.1097/00007890-199809270-00006
Purcell, D. F., Russell, S. M., Deacon, N. J., Brown, M. A., Hooker, D. J., & McKenzie, I. F. (1991). Alternatively spliced RNAs encode several isoforms of CD46 (MCP), a regulator of complement activation.Immunogenetics, 33 (5-6), 335-344. doi:10.1007/bf00216692
Rai, S., Arasteh, M., Jefferson, M., Pearson, T., Wang, Y., Zhang, W., . . . Wileman, T. (2019). The ATG5-binding and coiled coil domains of ATG16L1 maintain autophagy and tissue homeostasis in mice independently of the WD domain required for LC3-associated phagocytosis.Autophagy, 15 (4), 599-612. doi:10.1080/15548627.2018.1534507
Reggiori, F., & Ungermann, C. (2017). Autophagosome Maturation and Fusion. J Mol Biol, 429 (4), 486-496. doi:10.1016/j.jmb.2017.01.002
Reis, E. S., Mastellos, D. C., Hajishengallis, G., & Lambris, J. D. (2019). New insights into the immune functions of complement. Nat Rev Immunol, 19 (8), 503-516. doi:10.1038/s41577-019-0168-x
Richetta, C., Gregoire, I. P., Verlhac, P., Azocar, O., Baguet, J., Flacher, M., . . . Faure, M. (2013). Sustained autophagy contributes to measles virus infectivity. PLoS Pathog, 9 (9), e1003599. doi:10.1371/journal.ppat.1003599
Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D. (2010). Complement: a key system for immune surveillance and homeostasis.Nat Immunol, 11 (9), 785-797. doi:10.1038/ni.1923
Ricklin, D., Reis, E. S., Mastellos, D. C., Gros, P., & Lambris, J. D. (2016). Complement component C3 - The ”Swiss Army Knife” of innate immunity and host defense. Immunol Rev, 274 (1), 33-58. doi:10.1111/imr.12500
Romano, P. S., Gutierrez, M. G., Beron, W., Rabinovitch, M., & Colombo, M. I. (2007). The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell Microbiol, 9 (4), 891-909. doi:10.1111/j.1462-5822.2006.00838.x
Sanjuan, M. A., Dillon, C. P., Tait, S. W., Moshiach, S., Dorsey, F., Connell, S., . . . Green, D. R. (2007). Toll-like receptor signalling in macrophages links the autophagy pathway to phagocytosis. Nature, 450 (7173), 1253-1257. doi:10.1038/nature06421
Sentelle, R. D., Senkal, C. E., Jiang, W., Ponnusamy, S., Gencer, S., Selvam, S. P., . . . Ogretmen, B. (2012). Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol, 8 (10), 831-838. doi:10.1038/nchembio.1059
Shi, C. S., & Kehrl, J. H. (2008). MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages. J Biol Chem, 283 (48), 33175-33182. doi:10.1074/jbc.M804478200
Shi, C. S., Shenderov, K., Huang, N. N., Kabat, J., Abu-Asab, M., Fitzgerald, K. A., . . . Kehrl, J. H. (2012). Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol, 13 (3), 255-263. doi:10.1038/ni.2215
Sjoberg, A. P., Trouw, L. A., & Blom, A. M. (2009). Complement activation and inhibition: a delicate balance. Trends Immunol, 30 (2), 83-90. doi:S1471-4906(08)00271-8 [pii]
10.1016/j.it.2008.11.003
Sorbara, M. T., Foerster, E. G., Tsalikis, J., Abdel-Nour, M., Mangiapane, J., Sirluck-Schroeder, I., . . . Philpott, D. J. (2018). Complement C3 Drives Autophagy-Dependent Restriction of Cyto-invasive Bacteria. Cell Host Microbe, 23 (5), 644-652 e645. doi:10.1016/j.chom.2018.04.008
Tam, J. C., Bidgood, S. R., McEwan, W. A., & James, L. C. (2014). Intracellular sensing of complement C3 activates cell autonomous immunity. Science, 345 (6201), 1256070. doi:10.1126/science.1256070
Tattoli, I., Sorbara, M. T., Yang, C., Tooze, S. A., Philpott, D. J., & Girardin, S. E. (2013). Listeria phospholipases subvert host autophagic defenses by stalling pre-autophagosomal structures. EMBO J, 32 (23), 3066-3078. doi:10.1038/emboj.2013.234
Travassos, L. H., Carneiro, L. A., Ramjeet, M., Hussey, S., Kim, Y. G., Magalhaes, J. G., . . . Philpott, D. J. (2010). Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol, 11 (1), 55-62. doi:10.1038/ni.1823
Trouw, L. A., Blom, A. M., & Gasque, P. (2008). Role of complement and complement regulators in the removal of apoptotic cells. Mol Immunol, 45 (5), 1199-1207. doi:S0161-5890(07)00739-0 [pii]10.1016/j.molimm.2007.09.008
Tsai, Y. G., Wen, Y. S., Wang, J. Y., Yang, K. D., Sun, H. L., Liou, J. H., & Lin, C. Y. (2018). Complement regulatory protein CD46 induces autophagy against oxidative stress-mediated apoptosis in normal and asthmatic airway epithelium. Sci Rep, 8 (1), 12973. doi:10.1038/s41598-018-31317-5
Vazquez, C., & Horner, S. M. (2015). MAVS Coordination of Antiviral Innate Immunity. J Virol, 89 (14), 6974-6977. doi:10.1128/JVI.01918-14
Watada, H., & Fujitani, Y. (2015). Minireview: Autophagy in pancreatic beta-cells and its implication in diabetes. Mol Endocrinol, 29 (3), 338-348. doi:10.1210/me.2014-1367
Weidberg, H., Shpilka, T., Shvets, E., Abada, A., Shimron, F., & Elazar, Z. (2011). LC3 and GATE-16 N termini mediate membrane fusion processes required for autophagosome biogenesis. Dev Cell, 20 (4), 444-454. doi:10.1016/j.devcel.2011.02.006
Yue, Z., Horton, A., Bravin, M., DeJager, P. L., Selimi, F., & Heintz, N. (2002). A novel protein complex linking the delta 2 glutamate receptor and autophagy: implications for neurodegeneration in lurcher mice. Neuron, 35 (5), 921-933. doi:10.1016/s0896-6273(02)00861-9