The Role of the Beclin1 Complex in Rab9-Dependent Alternative Autophagy

Autophagy is a conserved catabolic pathway that degrades intracellular cargo through the lysosomal system. Canonically, this process is orchestrated by the autophagy-related (Atg)5-Atg7 conjugation system, which facilitates the formation of microtubule-associated protein 1 light chain 3 (LC3)-decorated double-membrane vesicles known as autophagosomes. However, accumulating evidence has revealed the existence of an Atg5-Atg7-independent, alternative autophagy pathway that still relies on upstream regulators such as the unc-51 like autophagy activating kinase 1 (Ulk1) kinase and the Beclin1 complex. In this review, we provide a comprehensive overview of the role of the Beclin1 complex in canonical autophagy and highlight its emerging importance in alternative autophagy. Notably, the recent identification of transmembrane protein 9 (TMEM9) as a lysosomal protein that interacts with Beclin1 to promote member RAS oncogene family 9 (Rab9)-dependent autophagosome formation has significantly advanced our understanding of alternative autophagy regulation. Furthermore, this Ulk1-Rab9-Beclin1-dependent mitophagy has been shown to mediate to mitochondrial quality control in the heart, thereby contributing to cardioprotection under ischemic and metabolic stress conditions. We further examine how the Beclin1 complex functions as a central scaffold in both canonical and alternative autophagy, with a focus on its modulation by novel factors such as TMEM9 and the potential therapeutic implications of these regulatory mechanisms.