The Mouse APG10 Homologue, an E2-like Enzyme for Apg12p Conjugation, Facilitates MAP-LC3 Modification

Abstract

Ubiquitylation and ubiquitylation-like protein conjugation mechanisms are essential to many cell-biological activities. Ubiquitin forms conjugates with target proteins via a threestep mechanism (1-3). First, ubiquitin is activated at its carboxyl-terminal glycine by the ubiquitin-activating (E1) 1 enzyme to form a conjugate through the active cysteine in the E1 enzyme via a thiol ester bond. Next, ubiquitin is transferred from the E1 enzyme to one of several ubiquitin-conjugating (E2) enzymes. In the last step, ubiquitin attaches to a lysine within a target protein via an isopeptide bond. This step is often catalyzed by a member of the ubiquitin protein ligase (E3 enzyme) family. With regard to other modifiers, Nedd8, SUMOs, Apg12p, and Apg8ps (Apg8p in yeast, and, MAP-LC3, GABARAP, and GATE-16 in mammals), each is modified by specific E1 and E2 enzymes, and conjugated with its target (4 -10). Of these modifiers, Apg12p and MAP-LC3 (Apg8p in yeast) cooperatively play an essential role in the dynamic membrane formation of the autophagosome during autophagy.

Autophagy and multivesicular bodies: two closely related partners

“…These studies led to the identification of a set of Atg (autophagy related) factors, which are evolutionary conserved. 10,56,57 Two ubiquitin-like conjugation systems that participate in a coordinated manner are necessary in early stages of autophagosome formation [58][59][60] (see Box 2). The first conjugation system produces the Atg12-Atg5 complex that is non-covalently associated with Atg16.…”

Lipidation of Atg8: How is substrate specificity determined without a canonical E3 enzyme?

“…1). [2][3][4][5][6][7][8] While Atg7 is a common E1 enzyme, Atg10 and Atg3 function as specific E2 enzymes for Atg12 and Atg8/LC3, respectively, to produce Atg12-Atg5 and Atg8-PE/LC3-PE conjugates, which are involved in the formation of autophagosomal membranes. 2,4,9,10 Atg5 is thought to be the sole target of Atg12, because immunoblotting anayses of Atg12 detect a single band of Atg12-Atg5 in addition to that of Atg12 alone.…”

Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK

“…For example, mice with the heterozygous mutant autophagy gene ATG6/BECN1 are prone to developing liver and lung tumors (13)(14)(15)(16)(17). Atg7 is known to serve a role in forming the autophagic vacuole (15)(16)(17)(18)(19). Conversely, the protective mechanism of autophagy can be utilized by cancer cells to overcome environmental stresses, including nutritional deficiency and the therapeutic use of anticancer drugs (19).…”

“…It has been revealed that several autophagy-related (Atg) genes were involved in autophagosome formation (12)(13)(14)(15)(16)(17). Autophagy is a protective mechanism that exerts antitumor action (13)(14)(15)(16)(17). For example, mice with the heterozygous mutant autophagy gene ATG6/BECN1 are prone to developing liver and lung tumors (13)(14)(15)(16)(17).…”

“…Autophagy is a protective mechanism that exerts antitumor action (13)(14)(15)(16)(17). For example, mice with the heterozygous mutant autophagy gene ATG6/BECN1 are prone to developing liver and lung tumors (13)(14)(15)(16)(17). Atg7 is known to serve a role in forming the autophagic vacuole (15)(16)(17)(18)(19).…”