Autophagosome biogenesis: From membrane growth to closure

Abstract

Autophagosome biogenesis involves de novo formation of a membrane that elongates to sequester cytoplasmic cargo and closes to form a double-membrane vesicle (an autophagosome). This process has remained enigmatic since its initial discovery >50 yr ago, but our understanding of the mechanisms involved in autophagosome biogenesis has increased substantially during the last 20 yr. Several key questions do remain open, however, including, What determines the site of autophagosome nucleation? What is the origin and lipid composition of the autophagosome membrane? How is cargo sequestration regulated under nonselective and selective types of autophagy? This review provides key insight into the core molecular mechanisms underlying autophagosome biogenesis, with a specific emphasis on membrane modeling events, and highlights recent conceptual advances in the field.

Lipids and membrane-associated proteins in autophagy

“…Once fused, acidic hydrolases in the lysosome can degrade the autophagic cargos and salvaged nutrients are released to the cytoplasm to be recycled by cells (Rong et al, 2012;Yu et al, 2018;Zhao and Zhang, 2019). The detailed molecular mechanisms of these proteins regulating different steps in autophagy have been recently reviewed in separate papers (Carlsson and Simonsen, 2015;Nakamura and Yoshimori, 2017;Reggiori and Ungermann, 2017;Dikic and Elazar, 2018;Mercer et al, 2018;Yu et al, 2018;Lai et al, 2019;Osawa et al, 2019a;Zhao and Zhang, 2019;Melia et al, 2020;Nishimura and Tooze, 2020). In Table 2, we summarized all of the known membrane-associated proteins, their functions, and their membrane-binding mechanisms in all steps of autophagy in a spatiotemporal way.…”

“…The phagophore membrane extends while engulfing substrates destined for degradation. Upon stimulation, macroautophagy probably needs to mobilize millions lipid molecules per cell for autophagosome growth (Melia et al, 2020). However, the molecular mechanism of how membrane elongation works is not fully understood.…”

“…So far, there are many works reviewing autophagy from various angles. In the past four years, there are review papers covering topics including functions of autophagy in disease (Dikic and Elazar, 2018;Thorburn, 2018;Levine and Kroemer, 2019), selective autophagy (Gatica et al, 2018;Johansen and Lamark, 2020), transcriptional/post-transcriptional regulation in autophagy (Delorme-Axford and Klionsky, 2018), interaction network and structure of autophagic proteins (Behrends et al, 2010;Hurley and Young, 2017;Suzuki et al, 2017;Lai et al, 2019), molecular mechanisms of autophagy (Hollenstein and Kraft, 2020;Melia et al, 2020;Nakatogawa, 2020), and specific steps of autophagy, including autophagosome formation (Carlsson and Simonsen, 2015;Dikic and Elazar, 2018;Mercer et al, 2018;Otomo et al, 2018;Yu et al, 2018;Ktistakis, 2019;Lai et al, 2019;Osawa et al, 2019a; References (Zinser and Daum, 1995;Daum and Vance, 1997) (Zambrano et al, 1975) (Zinser and Daum, 1995) (de Kroon et al, 1997) (Zinser and Daum, 1995) (Zambrano et al, 1975) (Zinser and Daum, 1995) (Wherrett and Huterer, 1972) (Schütter et al, 2020)…”

Endomembranes: Unsung Heroes of Mechanobiology?

“…Its function is to enclose damaged intracellular components in autophagosomes for their degradation by the lysosomal machinery. The various types and importance of the autophagic processes in maintaining proper cellular homeostasis have been thoroughly discussed elsewhere (He and Klionsky, 2009;Kawabata and Yoshimori, 2020;Melia et al, 2020).…”

Stress eating: Autophagy targets nuclear pore complexes

“…However, the mechanisms underlying the degradation of NPCs have remained elusive. Upon starvation or TORC1-inhibition, cells induce (macro)autophagy, a conserved degradative pathway, which results in the formation of double-membrane autophagosomes that engulf portions of the cytoplasm for degradation in the vacuole/ lysosome (6). Under these conditions, Lee et al and, in this issue, Tomioka et al show in budding yeast that autophagy can selectively target whole NPCs and nonassembled nucleoporins representative of all seven NPC subdomains for degradation (1,2).…”