1. Figure 1 The machinery of autophagy
Figure 1 | The machinery of autophagy. The degradation of cellular components by autophagy is coordinated by several protein complexes and vesicle fusion events. The membrane of the preautophagosome can originate from the endoplasmic reticulum (ER) or from other organelle structures and requires the serine/threonine-protein kinase ULK complex (comprising ULK1/2, autophagy-related protein [Atg] 13, FAK family kinase-interacting protein of 200 kDa [FIP200], and Atg101) and the movement of Beclin 1 away from apoptosis regulator Bcl-2 and into the phosphatidylinositol 3-kinase (PI3K) complex (comprising PI3K (class III), Beclin 1, and Atg14). The PI3K complex produces the phospholipid phosphatidylinositol 3-phosphate (PI(3)P), which attracts WD repeat domain phosphoinositide-interacting protein 1 (WIPI), Atg9, and Atg2 to the preautophagosome to position these key proteins ready to expand the membrane into an autophagosome. The Atg16L1 complex (comprising Atg16L1, Atg12, and Atg5) is recruited to the forming preautophagosome membrane by Ras-related protein (Rab) 33. Atg8 family proteins are incorporated into the membrane via Atg7-mediated and Atg3-mediated lipidation (PE), anchoring them into the double-membrane. Cellular cargo to be degraded is recruited into the autophagosome by adaptor proteins and bind to an Atg8 family member. The mechanism of autophagosome closure around the cargo is not well established, but might involve Atg2, Atg8, and Atg9. Autophagosomes can traffic along the cytoskeleton, and various proteins from the Rab (Rab5 and Rab7), UVRAG (ultraviolet radiation resistance-associated gene protein), and SNARE (soluble NSF attachment protein receptors and homologues; syntaxin [Stx] 7, Stx8, Stx17, vesicle transport through interaction with t-SNAREs homologue 1B [VTI1b], and vesicle-associated membrane protein [Vamp] 7) families are implicated in lysosome fusion. Lysosome-associated membrane glycoprotein (LAMP) 1 and LAMP2 have been implicated in various lysosomal functions, including maintaining lysosomal membrane integrity, autophagosome–lysosome fusion, and lysosome motility. The vacuolar- type H+ ATPase (V-ATPase) pumps protons across the lysosomal membrane to acidify the lumen. Hydrolases in the lysosome (blue circles) degrade the autophagosome contents. Chloroquine and bafilomycin are pharmacological agents used experimentally to block autophagosome–lysosome fusion (by neutralizing or preventing acidification) to assess autophagosome clearance.
Delbridge, L. M. D. et al. (2017) Myocardial stress and autophagy: mechanisms and potential therapies
Nat. Rev. Cardiol. doi: /nrcardio