SummaryCell growth (accumulation of mass) needs to be coordinated with metabolic processes that are required for the synthesis of macromolecules. The PI3-kinase/Akt signaling pathway induces cell growth via activation of complex 1 of the target of rapamycin (TORC1). Here we show that Akt-dependent lipogenesis requires mTORC1 activity. Furthermore, nuclear accumulation of the mature form of the sterol responsive element binding protein (SREBP1) and expression of SREBP target genes was blocked by the mTORC1 inhibitor rapamycin. We also show that silencing of SREBP blocks Akt-dependent lipogenesis and attenuates the increase in cell size in response to Akt activation in vitro. Silencing of dSREBP in flies caused a reduction in cell and organ size and blocked the induction of cell growth by dPI3K. Our results suggest that the PI3K/Akt/TOR pathway regulates protein and lipid biosynthesis in an orchestrated manner and that both processes are required for cell growth.

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A tale of two antiviral targets -and the COVID-19 drugs that bind themThe FDA is considering authorizations for Pfizer's paxlovid and Merck & Co.'s molnupiravir, the first two oral COVID-19 antivirals.COVID-19, for all of the problems it has created, has shown the unprecedented speed with which drug developers can move. Vaccines and bespoke antibodies were among the first responders on the COVID-19 scene, authorized just under 11 months from the release of the SARS-CoV-2 sequence. Now oral antivirals, from Pfizer and Merck & Co., are set to make their mark.Pfizer's contender, paxlovid, went from a compound in a freezer and optimization ideas on a drawing board to a regulatory submission in just 20 months. "It was a quick journey, " says Mikael Dolsten, Pfizer's chief scientific officer. "In the normal development of a small-molecule programme, that would take 8-10 years, " he notes.Merck's molnupiravir was already a preclinical candidate when COVID-19 struck, but also a beneficiary of a development sprint.The FDA is now considering both drugs for emergency use authorization (EUA). An FDA advisory committee voted 13 to 10 in favour of an EUA for molnupiravir on 30 November, preparing the way for an approval decision in the coming weeks. The EMA is reviewing molnupiravir too, and an application from Pfizer there is imminent.

The target of rapamycin (TOR) complex 1 (TORC1) signaling pathway is a critical regulator of translation and cell growth. To identify novel components of this pathway, we performed a kinome-wide RNA interference (RNAi) screen in Drosophila melanogaster S2 cells. RNAi targeting components of the p38 stress-activated kinase cascade prevented the cell size increase elicited by depletion of the TOR negative regulator TSC2. In mammalian and Drosophila tissue culture, as well as in Drosophila ovaries ex vivo, p38-activating stresses, such as H 2 O 2 and anisomycin, were able to activate TORC1. This stress-induced TORC1 activation could be blocked by RNAi against mitogen-activated protein kinase kinase 3 and 6 (MKK3/6) or by the overexpression of dominant negative Rags. Interestingly, p38 was also required for the activation of TORC1 in response to amino acids and growth factors. Genetic ablation either of p38b or licorne, its upstream kinase, resulted in small flies consisting of small cells. Mutants with mutations in licorne or p38b are nutrition sensitive; low-nutrient food accentuates the small-organism phenotypes, as well as the partial lethality of the p38b null allele. These data suggest that p38 is an important positive regulator of TORC1 in both mammalian and Drosophila systems in response to certain stresses and growth factors.