GLS1 Filament Formation Facilitates Glutamine Deprivation Induced Cell Death

Abstract

GLS1 orchestrates glutamine consumption and promotes cell proliferation when glutamine is abundant. Here, we show an unexpected role of GLS1 in facilitating apoptosis when glutamine is deprived. Mechanistically, GLS1 is a sensor for glutamate and glutamate in turn inhibits the conversion of GLS1 from dimer to a kind of micrometer-scale extremely-low-Km filamentous polymer in a dose-dependent manner. Glutamine deprivation decreases glutamate below a threshold, under which glutamate loses the inhibitory effect, allowing self-assembly of GLS1 into the super-activated filament. GLS1 filaments convert the already extremely low level of intracellular glutamine to glutamate to maintain mitochondrial glutamate homeostasis, exacerbating glutamine exhaustion. Glutamine deficiency then blocks the synthesis of asparagine and mitogenome-encoded proteins, leading to impairment of electron transfer, the burst of ROS, and the initiation of TOM40 oxidation-dependent apoptosis. Physiologically, we observed glutamine insufficiency and the GLS1 filaments in solid tumors. Importantly, expression of either K320A or a natural de novo S482C mutation of GLS1, both of which exist in the constitutively super-active filamentous form, dramatically suppresses cancer cell proliferation and tumorigenesis, suggesting that manipulation of GLS1 filament formation might be a potential strategy for cancer therapy.