SOD2 is a regulator of proteasomal degradation promoting an adaptive cellular starvation response.

Adaptation to changes in amino acid availability is crucial for cellular homeostasis, which requires an intricate orchestration of involved pathways. Some cancer cells can maintain cellular fitness upon amino acid shortage, which has a poorly understood mechanistic basis. Leveraging a genome-wide CRISPR-Cas9 screen, we find that superoxide dismutase 2 (SOD2) has a previously unrecognized dismutase-independent function. We demonstrate that SOD2 regulates global proteasomal protein degradation and promotes cell survival under conditions of metabolic stress in malignant cells through the E3 ubiquitin ligases UBR1 and UBR2. Consequently, inhibition of SOD2-mediated protein degradation highly sensitizes different cancer entities, including patient-derived xenografts, to amino acid depletion, highlighting the pathophysiological relevance of our findings. Our study reveals that SOD2 is a regulator of proteasomal protein breakdown upon starvation, which serves as an independent catabolic source of amino acids, a mechanism co-opted by cancer cells to maintain cellular fitness.