The Phosphatase CSW Controls Lifespan by Insulin Signaling and Metabolism throughout Adult Life in Drosophila

RUZZI, L.R.; SCHILMAN, P.E.; SAN MARTIN, A.; LEW, S.E.; GELB, B.D.; PAGANI, M.R.

Frontiers in Genetics

Frontiers

Año: 2020

Noonan syndrome and related disorders are caused by mutations in genes encoding for proteins of the RAS-ERK1/2 signaling pathway, which affect development by enhanced ERK1/2 activity. However, the mutations´ effects throughout adult life are unclear. In this study, we identify that the protein most commonly affected in Noonan syndrome, the phosphatase SHP2, known in Drosophila as corkscrew (CSW), controls lifespan, triglyceride levels and metabolism without affecting ERK signaling pathway. We found that CSW loss-of-function mutations extended lifespan by interacting with components of the insulin signaling pathway and impairing AKT activity in adult flies. By expressing csw RNAi in different organs, we determined that CSW extended lifespan by acting in organs that regulate energy availability, including gut, fat body and neurons. In contrast to control animals, loss of CSW leads to reduced homeostasis in metabolic rate during activity. Clinically relevant gain-of-function csw allele reduced lifespan, when expressed in fat body, but not in other tissues. However, overexpression of a wild-type allele did not affect lifespan, showing a specific effect of the gain-of-function allele independently of a gene dosage effect. We concluded that CSW normally regulates lifespan and mutations in SHP2 are expected to have critical effects throughout life by insulin-dependent mechanisms in addition to the well-known RAS-ERK1/2-dependent developmental alterations.