Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jul 4;221(7):e202203083.
doi: 10.1083/jcb.202203083. Epub 2022 Jun 14.

A guide to membrane atg8ylation and autophagy with reflections on immunity

Vojo Deretic  1   2 , Michael Lazarou  3   4
Affiliations

A guide to membrane atg8ylation and autophagy with reflections on immunity

Vojo Deretic et al. J Cell Biol. .

Abstract

The process of membrane atg8ylation, defined herein as the conjugation of the ATG8 family of ubiquitin-like proteins to membrane lipids, is beginning to be appreciated in its broader manifestations, mechanisms, and functions. Classically, membrane atg8ylation with LC3B, one of six mammalian ATG8 family proteins, has been viewed as the hallmark of canonical autophagy, entailing the formation of characteristic double membranes in the cytoplasm. However, ATG8s are now well described as being conjugated to single membranes and, most recently, proteins. Here we propose that the atg8ylation is coopted by multiple downstream processes, one of which is canonical autophagy. We elaborate on these biological outputs, which impact metabolism, quality control, and immunity, emphasizing the context of inflammation and immunological effects. In conclusion, we propose that atg8ylation is a modification akin to ubiquitylation, and that it is utilized by different systems participating in membrane stress responses and membrane remodeling activities encompassing autophagy and beyond.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Atg8ylation. Membrane atg8ylation includes a ubiquitylation-like cycle of covalent modifications of membrane lipids (PE and PS) by ATG8 proteins. Note three conjugation processes (labeled 1–3): membrane Atg8ylation (driven by ATG16L1-centered E3 ligase), protein Atg8ylation, and ATG12-ATG3 conjugation as an atg8ylation-independent branch. Modified after Kumar et al. (2021b).
Figure 2.
Figure 2.
Atg8ylation and its cell biological manifestations including canonical autophagy, noncanonical autophagy, and related nonautophagic processes. (A) Canonical autophagy as a classic output of atg8ylation and the process of double-membrane autophagosome formation with atg8ylation-independent and atg8ylation-dependent stages. ATG8-negative prophagophore (HyPAS) is defined by fusion of FIP200+ early-secretory pathway/cis-Golgi–derived membrane with ATG16L1+ endosomal membarnes. HyPAS converts to ATG8+ (usually referred as LC3+) phagophore, which sequesters the cargo and, upon ESCRT-catalyzed membrane closure, fuses with lysosomes leading to cargo degradation. (B and C) Noncanonical autophagy-related processes that do not involve formation of double-membrane autophagosomes and instead rely on atg8ylation of single-membrane organelles induced in response to membrane stress or other signals requiring membrane remodeling. (D) Processes utilizing atg8ylation that do not include canonical or noncanonical autophagy-related processes. Boxes indicate immunological processes associated with particular atg8ylation outputs. Details in the text.
Figure 3.
Figure 3.
Specific examples and circuitry of how atg8ylation controls different signaling and stress response processes at the lysosome. Note that both mTOR and AMPK as well as their regulatory elements are localized at the lysosome. AMPK positively regulates canonical autophagy, whereas mTOR negatively regulates this atg8ylation-associated process. Boxes 1–4 describe four of the expanding list of autophagy-independent atg8ylation-dependent processes. This includes control of AMPK, mTOR, and TFEB by mATG8s and atg8ylation (Boxes 1–3). Box 4–associated schematic depicts how increase in lumenal pH (phagosomes, organelles of the endolysosomal network) by the action of the influenza viroporin M2 that acts as an H+ channel or proton scavenging during superoxide production induce membrane atg8ylation (LC3 shown as an example of LAP and LAP-related processes). This occurs due to the increased recruitment of ATG16L1 via its direct binding to the V1 subunit of vacuolar H+-ATPase, upon elevated V1V0 assembly on membranes in response to neutralization of the lumenal pH. Further details in the text.
Figure 4.
Figure 4.
Signaling inputs into the systems regulating atg8ylation and canonical autophagy. To underscore that atg8ylation apparatus can act independently of canonical autophagy, the system is split into two parts (A and B). Atg8ylation E3 ligase centered upon ATG16L1 (A; see Fig. 1) and the FIP200 complex (B). For canonical autophagy, A and B come together (see Fig. 2). Three types of major inputs affecting components A or B or both are in peach-colored boxes (I–III) and fall in three categories: immune signals (I), signals coming from selective autophagy receptors (II), and metabolic signals (III). Immune signals are collected via PRRs assisted in many cases by immunity-related GTPases such as IRGM and often (but not exclusively) transduced via TBK1 to several components controlling atg8ylation and canonical autophagy apparatus. Cargo recognition by SLRs relays cargo capture, whereas SLRs can associate with FIP200 and in turn receive further signals from TBK1. Note that the ATG16L1 E3 ligase participates in FIP200 complex–independent standalone atg8ylation processes such as LAP and others (categorized in Fig. 1). Details in the text.
Figure 5.
Figure 5.
Atg8ylation and autophagy roles in innate immunity and immune cells. (A) Summary of anti-inflammatory action in disease contexts and animal models, and illustrations of proinflammatory signaling platforms targeted by atg8ylation or autophagy. (B) Direct antimicrobial action of atg8ylation and autophagy and microbial adaptations to counter or utilize atg8ylation or autophagy. (C) Roles of atg8ylation and autophagy in different types of immune cells, including homeostasis and immunometabolism. M1 and M2 refer to classically and alternatively activated macrophages. Details are given in the text.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ackermann, M., Anders H.J., Bilyy R., Bowlin G.L., Daniel C., De Lorenzo R., Egeblad M., Henneck T., Hidalgo A., Hoffmann M., et al. . 2021. Patients with COVID-19: In the dark-NETs of neutrophils. Cell Death Differ. 28:3125–3139. 10.1038/s41418-021-00805-z - DOI - PMC - PubMed
    1. Agrotis, A., von Chamier L., Oliver H., Kiso K., Singh T., and Ketteler R.. 2019. Human ATG4 autophagy proteases counteract attachment of ubiquitin-like LC3/GABARAP proteins to other cellular proteins. J. Biol. Chem. 294:12610–12621. 10.1074/jbc.AC119.009977 - DOI - PMC - PubMed
    1. Ahmad, L., Zhang S.Y., Casanova J.L., and Sancho-Shimizu V.. 2016. Human TBK1: A gatekeeper of neuroinflammation. Trends Mol. Med. 22:511–527. 10.1016/j.molmed.2016.04.006 - DOI - PMC - PubMed
    1. Alsaadi, R.M., Losier T.T., Tian W., Jackson A., Guo Z., Rubinsztein D.C., and Russell R.C.. 2019. ULK1-mediated phosphorylation of ATG16L1 promotes xenophagy, but destabilizes the ATG16L1 Crohn’s mutant. EMBO Re. 20:e46885. 10.15252/embr.201846885 - DOI - PMC - PubMed
    1. Andrade, R.M., Wessendarp M., Gubbels M.J., Striepen B., and Subauste C.S.. 2006. CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J. Clin. Investig. 116:2366–2377. 10.1172/JCI28796 - DOI - PMC - PubMed

Publication types

MeSH terms

Substances