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LC3-Associated Phagocytosis: Host Defense and Microbial Response

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LC3-Associated Phagocytosis: Host Defense and Microbial Response Available online at www.sciencedirect.com ScienceDirect LC3-associated phagocytosis: host defense and microbial response Sandeep Upadhyay and Jennifer A Philips The innate immune system has evolved to recognize diverse of canonical autophagy that selectively sequesters invading microbes and destroy them. At the same time, microbial microbes in a double membrane compartment so they can pathogens undermine immunity to cause disease. Here, we be routed to lysosomes. While LAP and xenophagy make highlight recent advances in understanding an antimicrobial use of shared components, such as certain ATG (autophagy pathway called LC3-associated phagocytosis (LAP), which related) proteins, they also have many unique require- combines features of autophagy with phagocytosis. Upon ments. For example, RUBCN/RUBICON promotes phagocytosis, many microbes, including bacteria, fungi, and LAP, whereas it interferes with xenophagy. Since xeno- parasites, are sequestered in an LC3-positive, single- phagy and LAP are critical for clearing microbes, it is not membrane bound compartment, a hallmark of LAP. LAP surprising that a number of medically important pathogens depends upon NADPH oxidase activity at the incipient interfere with these related processes. Given that there are phagosome and culminates in lysosomal trafficking and already many excellent reviews on the role of canonical microbial degradation. Most often LAP is an effective host autophagy in infection and immunity [2–4], here we high- defense, but some pathogens evade LAP or replicate light recent work on the LAP pathway and the mechanisms successfully in this microenvironment. Here, we review how by which pathogens undermine LAP. LAP targets microbial pathogens and strategies pathogens employ to circumvent LAP. Differences between LAP and xenophagy Address The molecular distinctions between canonical autophagy Division of Infectious Diseases, Department of Medicine, Department of and LAP have recently been reviewed in detail [1], and key Molecular Microbiology, Washington University School of Medicine, St. differences are illustrated in Figure 1. LAP occurs during Louis, MO 63110, USA phagocytosis when the engulfed cargo activates cellular Corresponding author: Philips, Jennifer A ([email protected]) receptors thatdrivetherecruitmentoftheNADPHoxidase and subsequentLC3-deliverytothephagosome.BothLAP and xenophagy are characterized by the association of Current Opinion in Immunology 2019, 60:81–90 lipidated LC3 (LC3-II) with microbe-containing compart- This review comes from a themed issue on Host pathogens ments. The conversion of LC3 to its phosphatidylethanol- Edited by Christina L Stallings and Michael S Glickman amine (PE)-conjugated form is orchestrated by ATG pro- For a complete overview see the Issue and the Editorial teins, including ATG5, ATG7, and ATG16L1 that are part of two ubiquitin-like ATG conjugation systems. A major Available online 24th June 2019 distinction between LAP and xenophagy is the source of https://doi.org/10.1016/j.coi.2019.04.012 the membrane in which LC3-II is incorporated. LAP 0952-7915/ã 2019 Elsevier Ltd. All rights reserved. begins with phagocytosis, whereas autophagy commences with the formation of a phagophore at the endoplasmic reticulum, a process that is under control of the autophagic initiating complex. The initiation complex is composed of the serine threonine kinase ULK1, and non-catalytic sub- units FIP200, ATG13, and ATG101. LAP does not rely on Introduction the formation of a double membrane phagophore or this machinery. Correspondingly, mTORC1andAMPK, which In the arms war with microbial pathogens, innate immune regulate autophagy initiation, do not appear to influence phagocytes deploy two autophagy-related pathways to LAP. Instead, during LAP, activation of the ATG conju- promote microbial degradation in lysosomes: LC3- gation systems depends upon the NADPH oxidase, which associated phagocytosis (LAP) and xenophagy. When is dispensable for xenophagy [5 ,6 ]. In some cases, as microbes activate certain pathogen recognition receptors, shown during Listeria and Salmonella infection, both LAP the LAP pathway utilizes autophagy proteins for a non- and xenophagy occur at the same time [7 ,8], and they can canonical function following phagocytosis to promote pha- be difficult to distinguish since both are defined by mem- gosome maturation. To evade phagolysosomal destruction, brane-associated LC3. LAP is established by nature of the some pathogens escape into the cytosol, while others dam- LC3-containing membrane (single, not double) and age the phagosome and inject microbial effectors into the genetic requirements (NADPH oxidase and RUBICON cytosol to disrupt lysosomal trafficking. In the face of versus the autophagy initiation complex). damaged phagosomes, host cells employ xenophagy, a form www.sciencedirect.com Current Opinion in Immunology 2019, 60:81–90 82 Host pathogens Figure 1 (a) Xenophagy (b) LAP DECTIN-1 FcγR TLR Pre-initiation complex NDP52 ATG4 Isolation membrane ATG7 ATG3 + ATG5 ATG12 ATG16L1 ATG5 NDP52/p62 ATG12 ATG16L1 NADPH NADP+ Ubiquitin PI3P Galectin LAPosome Glycan – O2 PE Phagolysosome fusion Current Opinion in Immunology Xenophagy and LC3-associated phagocytosis. (a) Xenophagy is a form of canonical autophagy, in which microbes are selectively captured into a double membrane autophagosome. When microbes disrupt the phagosomal membrane and gain access to the cytosol, damaged membrane remnants and bacterial surface proteins are ubiquitinated by host E3 ubiquitin ligases. Autophagy adaptors such as p62 and NDP52 bind ubiquitinated cargo and also LC3, thereby linking cargo to the emerging autophagosomal membrane. Damaged phagosomes also expose luminal glycans to the cytosol, which are recognized by cytosolic galectins, which also bind NDP52. Thus, autophagy adaptors target microbes and damaged phagosomes to the LC3-decorated double membrane compartment. Formation of this compartment requires the ULK1 pre-initiation complex (ULK1/2, FIP200, ATG13 and ATG101), which translocates from the cytoplasm to the endoplasmic reticulum. The ULK1 complex and the PI3K complex (ATG14L, BECLN1, VPS15, and VPS34) promote autophagy initiation during xenophagy. The autophagosome fuses with lysosomes to degrade sequestered microbes. (b) LAP is initiated on host phagocytes by engagement of surface receptors such as TLR2, DECTIN-1, FcgR, and TIM4 by bacteria, fungi, immune complexes, and dead cells, respectively. The signaling cascade initiated upon receptor engagement results in recruitment and assembly of NADPH oxidase complex on incipient phagosomes, which is stabilized by RUBICON. RUBICON is also a component of the PI3K complex phox (RUBICON, BECLN1, VPS15, and VPS34), which generates PI3P. PI3P binds the p40 subunit of the NADPH oxidase and is required for LAP. Current Opinion in Immunology 2019, 60:81–90 www.sciencedirect.com Role of LAP in innate immunity Upadhyay and Philips 83 LAP initiation do not appear to be involved in LAP [7 ,25,26]. For LAP serves as an innate defense against invading microbes, example during Salmonella typhimurium infection, some including a variety of bacteria, fungi, and parasites bacilli associate with autophagy adaptors, while the other (Table 1). LAP is activated by pathogen recognition recep- population is associated with diacylglycerol (DAG) tors (Toll-like receptors (TLRs), CLEC7/DECTIN1, [6 ,7 ]. Inhibition of p62 and DAG has an additive effect CLEC6A/DECTIN2, SLAM), as well as receptors that on LC3 trafficking, suggesting that these markers identify detect phosphatidylserine (TIM4) and antibodies distinct pathways [7 ]. How ATG16L1 is recruited to the (FcgR2a). Hence, apoptotic bodies, fungi, bacteria, outer microbial compartment is also different between the two membrane vesicles released by bacteria, and antibody- processes, as the C-terminal domain of ATG16L1 is essen- opsonized cargo trigger LAP [9 ,10 ,11 ,12,13]. Signaling tial during LAP but not canonical autophagy [27]. from these receptors through SYK kinase and protein kinase C (PKC) activates NADPH oxidase and LAPosome Studies on Aspergillus, Salmonella, and Listeria demonstrate formation [7 ,14,15]. Likely other receptors can activate that calcium and lipid signaling act upstream of NADPH LAP, and recently Listeria was shown to stimulate LAP oxidase recruitment during LAP (Figure 2). Kyrmizi et al. through the ß2 integrin Mac-1 receptor (ITGAM–ITGB2/ showed the importance of calcium–calmodulin signaling in Mac-1) [16 ]. A process that resembles LAP, with some regulating PI3K and NADPH oxidase during Aspergillus unconventional features, targets apicomplexan parasites, infection (discussed below in LAP evasion) [28 ]. Recent Plasmodium and Toxoplasma gondii, although the triggering work on Listeria points to the importance of ceramide. events are not well defined [17,18]. The induction of LAP Listeria, through its interaction with Mac-1, activates acid can also be influenced by cytokines, as an IFN-g effector sphingomyelinase (ASMase), which cleaves membrane +2 DAPK1, a Ca /calmodulin-regulated kinase, promotes the sphingomyelin into phosphorylcholine and ceramide formation of Aspergillus LAPosomes [19]. [16 ]. Ceramide-enriched membrane platforms serve as a scaffold for the NADPH oxidase. The resulting phos- phorylcholine may also serve as a substrate for host phos- LAP orchestration pholipase D (PLD). During S. typhimurium infection, the LAP depends upon the phosphatidylinositol 3-kinase sequential action of host PLD and
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