SOD2 Promotes Acute Leukemia Adaptation to Amino Acid Starvation Through the N-Degron Pathway

Amino acid availability is crucial for leukemia cell survival. However, mechanisms of adaptation to nutrient starvation remain poorly understood. Using a genome-wide CRISPR/Cas9 screen in T-ALL cells, we identified superoxide dismutase 2 (SOD2) as a regulator of the amino acid starvation response. Indeed, culturing SOD2-inhibited T-ALL cells in the absence of essential amino acids (EAA) or non-EAA, induced a significant decrease in cell viability by increasing levels of apoptosis. Importantly, sensitization appeared independent from known SOD2-associated pathways such as ROS signaling and glutamine anaplerosis. Using the Bioplex database (Huttlin et al., 2020), we identified UBR2, an E3 ubiquitin ligase in the N-degron pathway, as a unique binding partner of SOD2. Indeed, SOD2 and UBR2 co-immunoprecipitated, and SOD2 inhibition significantly decreased ubiquitin levels. These data collectively suggest that a complex formation with SOD2 positively regulates N-degron-mediated protein catabolism. The interaction of SOD2 and the N-degron pathway thus represents a previously unknown molecular adaptation of cancer cells in response to amino acid starvation.

Publication History

Article published online:
17 May 2022