DAF-18/PTEN protects LIN-35/Rb from CLP-1/CAPN-mediated cleavage to promote starvation resistance

Starvation resistance is a fundamental trait with profound influence on fitness and disease risk. DAF-18, the Caenorhabditis elegans ortholog of the tumor suppressor PTEN, promotes starvation resistance. PTEN is a dual phosphatase, and DAF-18 promotes starvation resistance as a lipid phosphatase by antagonizing insulin/IGF and PI3K signaling, activating the tumor suppressor DAF-16/FoxO. However, if or how DAF-18/PTEN protein-phosphatase activity promotes starvation resistance is unknown. Using genetic, genomic, bioinformatic, and biochemical approaches, we identified the C. elegans retinoblastoma/RB protein homolog, LIN-35/Rb, as a critical mediator of the effect of DAF-18/PTEN on starvation resistance. We show that DAF-18/PTEN protects LIN-35/Rb from cleavage by the μ-Calpain homolog CLP-1/CAPN, and that LIN-35/Rb together with the repressive DREAM complex promotes starvation resistance. We conclude that the tumor suppressors DAF-18/PTEN and LIN-35/Rb function in a linear pathway, with LIN-35/Rb and the rest of the DREAM complex functioning as a transcriptional effector of DAF-18/PTEN protein-phosphatase activity resulting in repression of germline gene expression. This work is significant for revealing a network of tumor suppressors that promote survival during cellular and developmental quiescence.