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