EAK-7 controls development and life span by regulating nuclear DAF-16/FoxO activity.

FoxO transcription factors control development and longevity in diverse species. Although FoxO regulation via changes in its subcellular localization is well established, little is known about how FoxO activity is regulated in the nucleus. Here, we show that the conserved C. elegans protein EAK-7 acts in parallel to the serine/threonine kinase AKT-1 to inhibit the FoxO transcription factor DAF-16. Loss of EAK-7 activity promotes diapause and longevity in a DAF-16/FoxO-dependent manner. Whereas akt-1 mutation activates DAF-16/FoxO by promoting its translocation from the cytoplasm to the nucleus, eak-7 mutation increases nuclear DAF-16/FoxO activity without influencing DAF-16/FoxO subcellular localization. Thus, EAK-7 and AKT-1 inhibit DAF-16/FoxO activity via distinct mechanisms. Our results implicate EAK-7 as a FoxO regulator and highlight the biological impact of a regulatory pathway that governs the activity of nuclear FoxO without altering its subcellular location.

Alam H ，Williams TW ，Dumas KJ ，Guo C ，Yoshina S ，Mitani S ，Hu PJ ... -  《-》

EAK proteins: novel conserved regulators of C. elegans lifespan.

Williams TW ，Dumas KJ ，Hu PJ 《Aging-US》

Caenorhabditis elegans EAK-3 inhibits dauer arrest via nonautonomous regulation of nuclear DAF-16/FoxO activity.

Zhang Y ，Xu J ，Puscau C ，Kim Y ，Wang X ，Alam H ，Hu PJ ... -  《-》

Effects of Caenorhabditis elegans sgk-1 mutations on lifespan, stress resistance, and DAF-16/FoxO regulation.

The AGC family serine-threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

Chen AT ，Guo C ，Dumas KJ ，Ashrafi K ，Hu PJ ... -  《-》

Activated AKT/PKB signaling in C. elegans uncouples temporally distinct outputs of DAF-2/insulin-like signaling.

Gami MS ，Iser WB ，Hanselman KB ，Wolkow CA ... -  《BMC DEVELOPMENTAL BIOLOGY》