Cell size and growth rate are modulated by TORC2-dependent signals

Abstract

SummaryThe size of all cells, from bacteria to vertebrates, is proportional to the growth rate set by nutrient availability, but the underlying mechanisms are unknown. Here, we show that nutrients modulate TORC2 signaling, and that cell size is proportional to TORC2 signaling in budding yeast. The TORC2 network controls production of ceramide lipids, which play roles in signaling. We discovered that ceramide-dependent signals control both growth rate and cell size. Thus, cells that can not make ceramides fail to modulate their growth rate or size in response to changes in nutrients. PP2A associated with the Rts1 regulatory subunit (PP2A Rts1 ) is embedded in a feedback loop that controls TORC2 signaling and plays an important role in mechanisms that modulate TORC2 signaling in response to nutrients. Together, the data suggest a model in which growth rate and cell size are mechanistically linked by ceramide-dependent signals arising from the TORC2 network.

Growth-dependent signals drive an increase in early G1 cyclin concentration to link cell cycle entry with cell growth

“…In both budding yeast and fission yeast, cells rapidly readjust the threshold amount of growth required for cell cycle progression when shifted to nutrient conditions that support different growth rates (Fantes and Nurse 1977;Johnston et al 1979;Lucena et al 2018). In fission yeast, the threshold appears to be readjusted within minutes.…”

“…Classic experiments in fission yeast suggest that the threshold amount of growth required for cell cycle progression is readjusted within minutes of a shift to new nutrient conditions (Fantes and Nurse 1977). A model that could explain the link between cell size and growth rate is that global signals that set growth rate also set the threshold amount of growth required for cell cycle progression (Lucena et al 2018). However, the mechanisms by which nutrient-dependent signals modulate growth thresholds remain largely unknown.…”

“…Distinguishing models will require a clear understanding of how changing concentrations of Cln3 and Whi5 influence cell cycle entry, and how the concentrations of Cln3 and Whi5 vary during growth and in response to changes in growth rate. However, there are conflicting reports on the behaviors of Cln3 and Whi5 during growth in G1 phase (Tyers et al 1993;Liu et al 2015;Schmoller et al 2015;Zapata et al 2014;Lucena et al 2018;Dorsey et al 2018;Blank et al 2018;Litsios et al 2019;Barber et al 2020). Most previous studies have used quantitative fluorescence microscopy to analyze protein behavior in living cells.…”

G1/S Transcription Factor Copy Number Is a Growth-Dependent Determinant of Cell Cycle Commitment in Yeast

“…The phosphatase PP2A connects other upstream nutrient signals to cell size. In the absence of TORC1 activity, the Rim15 kinase inactivates the PP2A Cdc55 isoform to enhance Whi5 phosphorylation (Talarek et al, 2017), while the PP2A Rts1 isoform inhibits the TORC2 complex and ceramide biosynthesis to adjust cell size (Lucena et al, 2018). The rate of cell growth may be transmitted to the Start machinery by the action of the Ydj1 chaperone on Cln3 (Aldea et al, 2017).…”

Organelle size scaling over embryonic development

“…Such positioning is dictated by both length-dependent microtubule (MT) forces and polarity domains at the cell cortex that alter such forces (Hasley, Chavez, Danilchik, Wuhr, & Pelegri, 2017;Minc & Piel, 2012;Pierre, Salle, Wuhr, & Minc, 2016;Xiao, Tong, Yang, & Wu, 2017). Other general regulators of cell size include nutrient availability (Leitao & Kellogg, 2017;Lucena et al, 2018;Vadia et al, 2017), signaling (Acebron, Karaulanov, Berger, Huang, & Niehrs, 2014;Luo, Liu, & Nassel, 2013), pressure and other mechanical forces (Perez Gonzalez et al, 2018;Pham et al, 2019), and expression and localization of cell cycle regulators (Keifenheim et al, 2017;Pan, Saunders, Flor-Parra, Howard, & Chang, 2014;Patterson, Rees, & Nurse, 2019;Schmoller & Skotheim, 2015;Zapata et al, 2014). Open questions remain about how these factors might regulate cell size in the early embryo.…”