A群鏈球菌(Group A Streptococcus，GAS）感染的主要致病原為化膿性鏈球菌（Streptococcus pyogenes），造成的症狀包含輕微且可自癒的表皮感染，以及壞死性筋膜炎和鏈球菌毒性休克症候群（streptococcal toxic shock syndrome，STSS）等危及生命的侵襲性疾病。當宿主受到細菌感染時，細胞會分泌活性含氧物（Reactive oxygen species，ROS）來清除胞內菌。其中，由NADPH氧化酶（NADPH oxidase）產生的活性含氧物除了抵禦感染之外，也參與調控細胞內的訊息傳遞。先前研究指出，活性含氧物會調控受感染的表皮細胞走向細胞凋亡，進而抑制A群鏈球菌增長。然而，面對血管內皮細胞時，A群鏈球菌則可以在細胞內存活並增殖，過多活性含氧物使細胞產生氧化壓力並導致內皮功能異常。因此，A群鏈球菌感染血管內皮層對後續引發的菌血症及敗血症影響舉足輕重。在本篇研究中，A群鏈球菌感染誘發NADPH氧化酶產生過量的活性含氧物會瓦解血管內皮屏障。活性含氧物也會活化PI3K/Akt訊號以關閉細胞自噬的典型路徑(Canonical autophagy）；同時，啟動LC3相關吞噬作用（LC3-associated phagocytosis，LAP）進而降解細胞間的緊密連接蛋白-1（ZO-1），由於LC3相關吞噬作用也涉及LC3的活化，因此該路徑屬於非典型的細胞自噬（Non-canonical autophagy）。在藥物實驗中，利用右美沙芬（dextromethorphan，DM）抑制NADPH氧化酶減緩細胞內氧化壓力後，具有恢復緊密連接蛋白-1表現量及預防緊密連接蛋白-1解離的成效；施加氯奎寧（chloroquine，CQ）抑制溶酶體酸化也能減緩緊密連接蛋白-1降解並維持細胞屏障的完整性。綜合上述，當A群鏈球菌感染內皮細胞後，由NADPH氧化酶產生的活性含氧物會推動LC3相關吞噬作用，吞噬緊密連接蛋白-1後將其降解，進而導致內皮細胞的通透性上升。

Group A streptococcal (GAS) infections, which caused by Streptococcus pyogenes range from self-limiting cutaneous illness to life-threatening invasive diseases, including necrotizing fasciitis, sepsis and streptococcal toxic shock syndrome. The infected cells can release reactive oxygen species (ROS) to eliminate intracellular pathogens. Among them, NAPDH oxidases (NOX)-derived ROS involve in not only host defense but signal transduction. In previous studies, epithelial cells infected with GAS undergo ROS-regulated apoptosis to inhibit the colonization. However, it has been shown that GAS can invade, survive and multiply in endothelial cells and the conquest of oxidative stress which may lead to endothelial dysfunction. Therefore, GAS-infected blood vessel endothelium may play a key role in the pathogenesis of invasive bacteremia and sepsis. In this study, excess ROS induced by GAS infection leading to endothelial barrier disruption was explored. The ROS-altered signal transduction can turn off the canonical autophagy via activating PI3k/Akt pathway. Degradation of tight junction protein zona occludens 1 (ZO-1) may be attributed to a non-canonical autophagy, LC3-associated phagocytosis (LAP) which was induced by NOX2-derived ROS. Treatment with a NOX inhibitor, dextromethorphan (DM), decreased the oxidative stress, restored the protein expression level of ZO-1 and protected ZO-1 from disassembly. Treatment with lysosomal acidification inhibitor, chloroquine (CQ), attenuated the degradation of ZO-1 protein and maintained the barrier integrity. Taken together, NOX-derived ROS might trigger LAP formation to engulf tight junction protein ZO-1 followed by degradation leading to endothelial hyperpermeability.

1. Steer AC, Lamagni T, Curtis N, Carapetis JR. 2012. Invasive group a streptococcal disease: epidemiology, pathogenesis and management. Drugs 72:1213-27.
2. Stevens DL. 2000. Streptococcal toxic shock syndrome associated with necrotizing fasciitis. Annu Rev Med 51:271-88.
3. Carapetis JR, Steer AC, Mulholland EK, Weber M. 2005. The global burden of group A streptococcal diseases. Lancet Infect Dis 5:685-94.
4. Al-Hamad AM. 2015. Streptococcal throat. Therapeutic options and macrolide resistance. Saudi Med J 36:1128-9.
5. Passàli D, Lauriello M, Passàli GC, Passàli FM, Bellussi L. 2007. Group A Streptococcus and its antibiotic resistance. Acta Otorhinolaryngol Ital 27:27-32.
6. Brook I. 2017. Treatment challenges of group A beta-hemolytic streptococcal pharyngo-tonsillitis. Int Arch Otorhinolaryngol 21:286-296.
7. Walker MJ, Barnett TC, McArthur JD, Cole JN, Gillen CM, Henningham A, Sriprakash KS, Sanderson-Smith ML, Nizet V. 2014. Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin Microbiol Rev 27:264-301.
8. Kanwal S, Vaitla P. 2020. Streptococcus pyogenes, StatPearls. StatPearls Publishing Copyright © 2020, StatPearls Publishing LLC., Treasure Island (FL).
9. Henningham A, Gillen CM, Walker MJ. 2013. Group a streptococcal vaccine candidates: potential for the development of a human vaccine. Curr Top Microbiol Immunol 368:207-42.
10. Henningham A, Döhrmann S, Nizet V, Cole JN. 2015. Mechanisms of group A Streptococcus resistance to reactive oxygen species. FEMS Microbiol Rev 39:488-508.
11. Kwinn LA, Nizet V. 2007. How group A Streptococcus circumvents host phagocyte defenses. Future Microbiol 2:75-84.
12. Molinari G, Chhatwal GS. 1998. Invasion and survival of Streptococcus pyogenes in eukaryotic cells correlates with the source of the clinical isolates. J Infect Dis 177:1600-7.
13. Lu SL, Kawabata T, Cheng YL, Omori H, Hamasaki M, Kusaba T, Iwamoto R, Arimoto H, Noda T, Lin YS, Yoshimori T. 2017. Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes. PLoS Pathog 13:e1006444.
14. Sharma V, Verma S, Seranova E, Sarkar S, Kumar D. 2018. Selective Autophagy and xenophagy in infection and disease. Front Cell Dev Biol 6:147.
15. Mao K, Klionsky DJ. 2017. Xenophagy: A battlefield between host and microbe, and a possible avenue for cancer treatment. Autophagy 13:223-224.
16. Ochel A, Rohde M, Chhatwal GS, Talay SR. 2014. The M1 protein of Streptococcus pyogenes triggers an innate uptake mechanism into polarized human endothelial cells. J Innate Immun 6:585-96.
17. Johansson L, Thulin P, Low DE, Norrby-Teglund A. 2010. Getting under the skin: the immunopathogenesis of Streptococcus pyogenes deep tissue infections. Clin Infect Dis 51:58-65.
18. Hird B, Byrne K. 1994. Gangrenous streptococcal myositis: case report. J Trauma 36:589-91.
19. Siggins MK, Lynskey NN, Lamb LE, Johnson LA, Huse KK, Pearson M, Banerji S, Turner CE, Woollard K, Jackson DG, Sriskandan S. 2020. Extracellular bacterial lymphatic metastasis drives Streptococcus pyogenes systemic infection. Nat Commun 11:4697.
20. Stevens DL, Bryant AE. 2017. Necrotizing soft-tissue infections. N Engl J Med 377:2253-2265.
21. Saetre T, Höiby EA, Kähler H, Lyberg T. 2000. Changed expression of leukocyte adhesion molecules and increased production of reactive oxygen species caused by Streptococcus pyogenes in human whole blood. Apmis 108:573-80.
22. Montezano AC, Touyz RM. 2012. Reactive oxygen species and endothelial function--role of nitric oxide synthase uncoupling and Nox family nicotinamide adenine dinucleotide phosphate oxidases. Basic Clin Pharmacol Toxicol 110:87-94.
23. Lambeth JD. 2004. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181-9.
24. Brown DI, Griendling KK. 2009. Nox proteins in signal transduction. Free Radic Biol Med 47:1239-53.
25. Saetre T, Höiby EA, Aspelin T, Lermark G, Egeland T, Lyberg T. 2000. Aminoethyl-isothiourea, a nitric oxide synthase inhibitor and oxygen radical scavenger, improves survival and counteracts hemodynamic deterioration in a porcine model of streptococcal shock. Crit Care Med 28:2697-706.
26. Cheng YL, Kuo CF, Lu SL, Hiroko O, Wu YN, Hsieh CL, Noda T, Wu SR, Anderson R, Lin CF, Chen CL, Wu JJ, Lin YS. 2019. Group A streptococcus induces LAPosomes via SLO/β1 integrin/NOX2/ROS pathway in endothelial cells that are ineffective in bacterial killing and suppress xenophagy. mBio 10:e02148-19.
27. Bedard K, Krause KH. 2007. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev 87:245-313.
28. Balaban RS, Nemoto S, Finkel T. 2005. Mitochondria, oxidants, and aging. Cell 120:483-95.
29. Gonzalez FJ. 2005. Role of cytochromes P450 in chemical toxicity and oxidative stress: studies with CYP2E1. Mutat Res 569:101-10.
30. Schrader M, Fahimi HD. 2004. Mammalian peroxisomes and reactive oxygen species. Histochem Cell Biol 122:383-93.
31. Cecarini V, Gee J, Fioretti E, Amici M, Angeletti M, Eleuteri AM, Keller JN. 2007. Protein oxidation and cellular homeostasis: Emphasis on metabolism. Biochim Biophys Acta 1773:93-104.
32. Song YS, Lee BY, Hwang ES. 2005. Dinstinct ROS and biochemical profiles in cells undergoing DNA damage-induced senescence and apoptosis. Mech Ageing Dev 126:580-90.
33. Burdon RH. 1995. Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. Free Radic Biol Med 18:775-94.
34. Sauer H, Neukirchen W, Rahimi G, Grünheck F, Hescheler J, Wartenberg M. 2004. Involvement of reactive oxygen species in cardiotrophin-1-induced proliferation of cardiomyocytes differentiated from murine embryonic stem cells. Exp Cell Res 294:313-24.
35. Hidalgo C, Sánchez G, Barrientos G, Aracena-Parks P. 2006. A transverse tubule NADPH oxidase activity stimulates calcium release from isolated triads via ryanodine receptor type 1 S -glutathionylation. J Biol Chem 281:26473-82.
36. Abid MR, Kachra Z, Spokes KC, Aird WC. 2000. NADPH oxidase activity is required for endothelial cell proliferation and migration. FEBS Lett 486:252-6.
37. Konukoglu D, Uzun H. 2017. Endothelial dysfunction and hypertension. Adv Exp Med Biol 956:511-540.
38. Collins P, Maas A, Prasad M, Schierbeck L, Lerman A. 2020. Endothelial vascular function as a surrogate of vascular risk and aging in women. Mayo Clin Proc 95:541-553.
39. Walshe TE, dela Paz NG, D'Amore PA. 2013. The role of shear-induced transforming growth factor-β signaling in the endothelium. Arterioscler Thromb Vasc Biol 33:2608-17.
40. Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA. 2016. Endothelial fluid shear stress sensing in vascular health and disease. J Clin Invest 126:821-8.
41. Shimokawa H, Matoba T. 2004. Hydrogen peroxide as an endothelium-derived hyperpolarizing factor. Pharmacol Res 49:543-9.
42. Matoba T, Shimokawa H. 2003. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in animals and humans. J Pharmacol Sci 92:1-6.
43. Kuroki M, Voest EE, Amano S, Beerepoot LV, Takashima S, Tolentino M, Kim RY, Rohan RM, Colby KA, Yeo KT, Adamis AP. 1996. Reactive oxygen intermediates increase vascular endothelial growth factor expression in vitro and in vivo. J Clin Invest 98:1667-75.
44. Morgan MJ, Liu ZG. 2011. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 21:103-15.
45. Mussbacher M, Salzmann M, Brostjan C, Hoesel B, Schoergenhofer C, Datler H, Hohensinner P, Basílio J, Petzelbauer P, Assinger A, Schmid JA. 2019. Cell type-specific roles of NF-κB linking inflammation and thrombosis. Front Immunol 10:85.
46. Cerutti C, Ridley AJ. 2017. Endothelial cell-cell adhesion and signaling. Exp Cell Res 358:31-38.
47. Kellner M, Noonepalle S, Lu Q, Srivastava A, Zemskov E, Black SM. 2017. ROS signaling in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Adv Exp Med Biol 967:105-137.
48. Endemann DH, Schiffrin EL. 2004. Endothelial dysfunction. J Am Soc Nephrol 15:1983-92.
49. Hadi HA, Carr CS, Al Suwaidi J. 2005. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag 1:183-98.
50. Armstrong SM, Darwish I, Lee WL. 2013. Endothelial activation and dysfunction in the pathogenesis of influenza A virus infection. Virulence 4:537-42.
51. Takatsuka H, Wakae T, Mori A, Okada M, Fujimori Y, Takemoto Y, Okamoto T, Kanamaru A, Kakishita E. 2003. Endothelial damage caused by cytomegalovirus and human herpesvirus-6. Bone Marrow Transplant 31:475-9.
52. Huertas A, Montani D, Savale L, Pichon J, Tu L, Parent F, Guignabert C, Humbert M. 2020. Endothelial cell dysfunction: a major player in SARS-CoV-2 infection (COVID-19)? Eur Respir J 56.
53. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, Mehra MR, Schuepbach RA, Ruschitzka F, Moch H. 2020. Endothelial cell infection and endotheliitis in COVID-19. Lancet 395:1417-1418.
54. Bryant AE, Chen RY, Nagata Y, Wang Y, Lee CH, Finegold S, Guth PH, Stevens DL. 2000. Clostridial gas gangrene. I. Cellular and molecular mechanisms of microvascular dysfunction induced by exotoxins of Clostridium perfringens. J Infect Dis 182:799-807.
55. Bryant AE, Bayer CR, Chen RY, Guth PH, Wallace RJ, Stevens DL. 2005. Vascular dysfunction and ischemic destruction of tissue in Streptococcus pyogenes infection: the role of streptolysin O-induced platelet/neutrophil complexes. J Infect Dis 192:1014-22.
56. Bazzoni G, Dejana E. 2004. Endothelial cell-to-cell junctions: molecular organization and role in vascular homeostasis. Physiol Rev 84:869-901.
57. Balda MS, Matter K. 2008. Tight junctions at a glance. J Cell Sci 121:3677-82.
58. Guillemot L, Paschoud S, Pulimeno P, Foglia A, Citi S. 2008. The cytoplasmic plaque of tight junctions: a scaffolding and signalling center. Biochim Biophys Acta 1778:601-13.
59. Tornavaca O, Chia M, Dufton N, Almagro LO, Conway DE, Randi AM, Schwartz MA, Matter K, Balda MS. 2015. ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J Cell Biol 208:821-38.
60. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T. 2008. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol 172:521-33.
61. Sonoda N, Furuse M, Sasaki H, Yonemura S, Katahira J, Horiguchi Y, Tsukita S. 1999. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands: Evidence for direct involvement of claudins in tight junction barrier. J Cell Biol 147:195-204.
62. Chen HR, Chuang YC, Chao CH, Yeh TM. 2015. Macrophage migration inhibitory factor induces vascular leakage via autophagy. Biol Open 4:244-52.
63. Wang C, Puerta-Guardo H, Biering SB, Glasner DR, Tran EB, Patana M, Gomberg TA, Malvar C, Lo NTN, Espinosa DA, Harris E. 2019. Endocytosis of flavivirus NS1 is required for NS1-mediated endothelial hyperpermeability and is abolished by a single N-glycosylation site mutation. PLoS Pathog 15:e1007938.
64. Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. 2003. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 300:1430-4.
65. Deretic V, Saitoh T, Akira S. 2013. Autophagy in infection, inflammation and immunity. Nat Rev Immunol 13:722-37.
66. Karanasios E, Walker SA, Okkenhaug H, Manifava M, Hummel E, Zimmermann H, Ahmed Q, Domart MC, Collinson L, Ktistakis NT. 2016. Autophagy initiation by ULK complex assembly on ER tubulovesicular regions marked by ATG9 vesicles. Nat Commun 7:12420.
67. Heckmann BL, Green DR. 2019. LC3-associated phagocytosis at a glance. J Cell Sci 132.
68. Lai SC, Devenish RJ. 2012. LC3-associated phagocytosis (LAP): Connections with host autophagy. Cells 1:396-408.
69. Nelson GE, Pondo T, Toews KA, Farley MM, Lindegren ML, Lynfield R, Aragon D, Zansky SM, Watt JP, Cieslak PR, Angeles K, Harrison LH, Petit S, Beall B, Van Beneden CA. 2016. Epidemiology of invasive group A streptococcal infections in the United States, 2005-2012. Clin Infect Dis 63:478-86.
70. Lamagni TL, Neal S, Keshishian C, Powell D, Potz N, Pebody R, George R, Duckworth G, Vuopio-Varkila J, Efstratiou A. 2009. Predictors of death after severe Streptococcus pyogenes infection. Emerg Infect Dis 15:1304-7.
71. Stevens DL, Tanner MH, Winship J, Swarts R, Ries KM, Schlievert PM, Kaplan E. 1989. Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 321:1-7.
72. O'Loughlin RE, Roberson A, Cieslak PR, Lynfield R, Gershman K, Craig A, Albanese BA, Farley MM, Barrett NL, Spina NL, Beall B, Harrison LH, Reingold A, Van Beneden C. 2007. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000-2004. Clin Infect Dis 45:853-62.
73. Liu PY, Lin CC, Tsai WC, Li YH, Lin LJ, Shi GY, Hong JS, Chen JH, Wu HL. 2008. Treatment with dextromethorphan improves endothelial function, inflammation and oxidative stress in male heavy smokers. J Thromb Haemost 6:1685-92.
74. Li MH, Luo YH, Lin CF, Chang YT, Lu SL, Kuo CF, Hong JS, Lin YS. 2011. Dextromethorphan efficiently increases bactericidal activity, attenuates inflammatory responses, and prevents group a streptococcal sepsis. Antimicrob Agents Chemother 55:967-73.
75. Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. 2004. Autophagy defends cells against invading group A Streptococcus. Science 306:1037-40.
76. Lu SL, Kuo CF, Chen HW, Yang YS, Liu CC, Anderson R, Wu JJ, Lin YS. 2015. Insufficient acidification of autophagosomes facilitates group A Streptococcus survival and growth in endothelial cells. mBio 6:e01435-15.
77. Aikawa C, Nozawa T, Maruyama F, Tsumoto K, Hamada S, Nakagawa I. 2010. Reactive oxygen species induced by Streptococcus pyogenes invasion trigger apoptotic cell death in infected epithelial cells. Cell Microbiol 12:814-30.
78. Ginsburg I, Varani J. 1993. Interaction of viable group A streptococci and hydrogen peroxide in killing of vascular endothelial cells. Free Radic Biol Med 14:495-500.
79. Singel KL, Segal BH. 2016. NOX2-dependent regulation of inflammation. Clin Sci (Lond) 130:479-90.
80. Yang S, Yang J, Yang Z, Chen P, Fraser A, Zhang W, Pang H, Gao X, Wilson B, Hong JS, Block ML. 2006. Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP4-6 are neuroprotective through inhibition of NADPH oxidase: potent regulators of microglia-mediated oxidative stress. J Pharmacol Exp Ther 319:595-603.
81. Rho SS, Ando K, Fukuhara S. 2017. Dynamic regulation of vascular permeability by vascular endothelial cadherin-mediated endothelial cell-cell junctions. J Nippon Med Sch 84:148-159.
82. Gavard J. 2013. Endothelial permeability and VE-cadherin: a wacky comradeship. Cell Adh Migr 7:455-61.
83. Loor G, Kondapalli J, Schriewer JM, Chandel NS, Vanden Hoek TL, Schumacker PT. 2010. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis. Free Radic Biol Med 49:1925-36.
84. Criddle DN, Gillies S, Baumgartner-Wilson HK, Jaffar M, Chinje EC, Passmore S, Chvanov M, Barrow S, Gerasimenko OV, Tepikin AV, Sutton R, Petersen OH. 2006. Menadione-induced reactive oxygen species generation via redox cycling promotes apoptosis of murine pancreatic acinar cells. J Biol Chem 281:40485-92.
85. Giannotta M, Trani M, Dejana E. 2013. VE-cadherin and endothelial adherens junctions: active guardians of vascular integrity. Dev Cell 26:441-54.
86. Grimsley-Myers CM, Isaacson RH, Cadwell CM, Campos J, Hernandes MS, Myers KR, Seo T, Giang W, Griendling KK, Kowalczyk AP. 2020. VE-cadherin endocytosis controls vascular integrity and patterning during development. J Cell Biol 219.
87. Rohde M, Müller E, Chhatwal GS, Talay SR. 2003. Host cell caveolae act as an entry-port for group A streptococci. Cell Microbiol 5:323-42.
88. Clapp BR, Hingorani AD, Kharbanda RK, Mohamed-Ali V, Stephens JW, Vallance P, MacAllister RJ. 2004. Inflammation-induced endothelial dysfunction involves reduced nitric oxide bioavailability and increased oxidant stress. Cardiovasc Res 64:172-8.
89. Tsai PJ, Chen YH, Hsueh CH, Hsieh HC, Liu YH, Wu JJ, Tsou CC. 2006. Streptococcus pyogenes induces epithelial inflammatory responses through NF-kappaB/MAPK signaling pathways. Microbes Infect 8:1440-9.
90. Bem JL, Peck R. 1992. Dextromethorphan. An overview of safety issues. Drug Saf 7:190-9.
91. Dejana E, Orsenigo F, Lampugnani MG. 2008. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 121:2115-22.
92. Gory-Fauré S, Prandini MH, Pointu H, Roullot V, Pignot-Paintrand I, Vernet M, Huber P. 1999. Role of vascular endothelial-cadherin in vascular morphogenesis. Development 126:2093-102.
93. Huber P, Bouillot S, Elsen S, Attrée I. 2014. Sequential inactivation of Rho GTPases and Lim kinase by Pseudomonas aeruginosa toxins ExoS and ExoT leads to endothelial monolayer breakdown. Cell Mol Life Sci 71:1927-41.
94. Sprenkeler EG, Gresnigt MS, van de Veerdonk FL. 2016. LC3-associated phagocytosis: a crucial mechanism for antifungal host defence against Aspergillus fumigatus. Cell Microbiol 18:1208-16.
95. Herb M, Gluschko A, Schramm M. 2020. LC3-associated phagocytosis - The highway to hell for phagocytosed microbes. Semin Cell Dev Biol 101:68-76.
96. Asare PF, Roscioli E, Hurtado PR, Tran HB, Mah CY, Hodge S. 2020. LC3-associated phagocytosis (LAP): A potentially influential mediator of efferocytosis-related tumor progression and aggressiveness. Front Oncol 10:1298.
97. Heckmann BL, Boada-Romero E, Cunha LD, Magne J, Green DR. 2017. LC3-associated phagocytosis and inflammation. J Mol Biol 429:3561-3576.
98. Cunha LD, Yang M, Carter R, Guy C, Harris L, Crawford JC, Quarato G, Boada-Romero E, Kalkavan H, Johnson MDL, Natarajan S, Turnis ME, Finkelstein D, Opferman JT, Gawad C, Green DR. 2018. LC3-associated phagocytosis in myeloid cells promotes tumor immune tolerance. Cell 175:429-441.e16.
99. Martinez J, Malireddi RK, Lu Q, Cunha LD, Pelletier S, Gingras S, Orchard R, Guan JL, Tan H, Peng J, Kanneganti TD, Virgin HW, Green DR. 2015. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol 17:893-906.
100. Wong SW, Sil P, Martinez J. 2018. Rubicon: LC3-associated phagocytosis and beyond. Febs J 285:1379-1388.