Atg8 orchestrates stress-responsive chromatin programs across immunity and metabolism

Organisms must coordinate transcriptional responses to immune and metabolic stress, often within the same tissue. In Drosophila and mammals, adipose tissue integrates these signals by mounting antimicrobial defense during acute infection and remodeling lipid metabolism under chronic nutrient surplus. How one cell-biological system supports both functions, and through what molecular machinery, remains incompletely understood. Atg8/LC3, classically defined by canonical autophagy, has emerging non-canonical roles in nuclear gene regulation, raising the possibility that it contributes to stress-coordinated transcription beyond cargo turnover. Using unbiased CUT&RUN in adult Drosophila nuclei, we find that endogenous Atg8 exhibits broad chromatin occupancy at immune, metabolic, and autophagy loci, and accumulates in nuclei under prolonged high-sugar diet (HSD) and acute Gram-positive infection. We identify two conserved Atg8-interacting motifs (AIMs) within the Rel homology domain of NF-κB/Dif. Flies carrying CRISPR-engineered AIM-mutant Dif are highly susceptible to both infection and chronic HSD, establishing a physiological requirement for intact Dif AIMs. AIM-mutant Dif shows impaired infection-induced nuclear accumulation, suggesting that Atg8 contributes to both Dif cytoplasmic-to-nuclear shuttling and nuclear function. Unbiased comparison of Atg8 chromatin occupancy across HSD and infection further reveals shared and divergent motif grammar, positioning Atg8 as a stress-responsive chromatin cofactor for immune and metabolic transcription. Together, these findings expand the functional landscape of Atg8/LC3 beyond canonical autophagy and reveal that autophagy machinery contributes to stress-specific transcriptional complex assembly. AIM/LIR-mediated interactions, exemplified by Dif, represent one such interface, while additional mechanisms likely underlie Atg8’s broader chromatin engagement at loci enriched for transcription factor motifs whose cognate factors lack known AIM/LIRs. We propose that Atg8/LC3-mediated coordination of immune and metabolic transcription is a general principle by which cells integrate diverse stress signals, with implications for obesity, chronic inflammation, and other disease states in which immune and metabolic dysregulation converge.