Autophagy, an evolutionarily conserved and tightly controlled process in eukaryotic cells, allows them to respond to stress by selectively eliminating dysfunctional or unwanted materials to promote metabolic flexibility and maintain homeostasis. While autophagy is orchestrated by different autophagy (ATG)-related genes, whose regulation varies considerably according to tissue type and developmental stage. In this review, we investigate how regardless of the different players involved in autophagy, ATG5 emerges as a unique, highly conserved, critical molecule that acts as a central rheostat to control the stem cell fate, metabolic adaptability, and govern the immune signature pattern in cells. The journey of ATG5 modulation from physiological developmental variation to pathological scenario brings out the translational impact of ATG5. On the one hand, ATG5 promotes exit from the pluripotent state by c-Myc degradation during differentiation of specific lineages (involved in neurogenesis, adipogenesis, and hematopoiesis), while on the other hand, it has a critical involvement in metabolic circuitry via rewiring autophagy through modulation of lipophagy, mitophagy, and acetyl-CoA epigenetics. Taken together, this work summarizes new findings that centrally place ATG5 as a driver that engineers a coordinated crosstalk between the metabolic state and cell fate decisions and immune responses. These insights position ATG5 as a critical and therapeutic target for developmental disorders, cancer, and immune-metabolic diseases.
