A Conserved PP2A Regulatory Subunit Enforces Proportional Relationships Between Cell Size and Growth Rate

Abstract

Cell size is proportional to growth rate. Thus, cells growing rapidly in rich nutrients can be nearly twice the size of cells growing slowly in poor nutrients. This proportional relationship appears to hold across all orders of life, yet the underlying mechanisms are unknown. In budding yeast, most growth occurs during mitosis, and the proportional relationship between cell size and growth rate is therefore enforced primarily by modulating growth in mitosis. When growth is slow, the duration of mitosis is increased to allow more time for growth, yet the amount of growth required to complete mitosis is reduced, which leads to the birth of small daughter cells. Previous studies have found that Rts1, a member of the conserved B56 family of protein phosphatase 2A regulatory subunits, works in a TORC2 signaling network that influences cell size and growth rate. However, it was unclear whether Rts1 influences cell growth and size in mitosis. Here, we show that Rts1 is required for the proportional relationship between cell size and growth rate during mitosis. Moreover, nutrients and Rts1 influence the duration and extent of growth in mitosis via Wee1 and Pds1/securin, two conserved regulators of mitotic progression. Together, the data are consistent with a model in which global signals that set growth rate also set the critical amount of growth required for cell cycle progression, which would provide a simple mechanistic explanation for the proportional relationship between cell size and growth rate.

Growth-Dependent Activation of Protein Kinases Suggests a Mechanism for Measuring Cell Growth

“…As reported previously, swe1∆ caused reduced growth rate, which is thought to be due to the decreased size of mother cells (Fig. S2 A) (Leitao et al 2019).…”

“…Several observations demonstrated that Gin4 and Hsl1 do not work solely via Swe1. Previous studies found that swe1∆ cells have a shorter metaphase than wild type cells (Lianga et al 2013;Leitao et al 2019). Here, we found that swe1∆ reduced the duration of metaphase in gin4-AID hsl1-AID cells, but it did not make the duration of metaphase in these cells shorter than metaphase in wild type cells, indicating that acute loss of Gin4 and Hsl1 still influenced the duration of metaphase in swe1∆ cells.…”

“…The budding yeast homolog of Wee1 is referred to as Swe1. Additional studies have shown that Swe1 influences the timing of mitotic entry as well as the duration of metaphase by regulating this inhibitory phosphorylation of Cdk1 (Harvey and Kellogg 2003;Lianga et al 2013;Leitao et al 2019). We therefore tested whether Gin4 and Hsl1 influence the duration of metaphase and cell size via Swe1.…”

Conserved Ark1-related kinases function in a TORC2 signaling network

“…In cells that span all orders of life, the growth rate of proliferating cells is proportional to nutrient availability, and cell size is proportional to growth rate ( Schaechter et al , 1958 ; Hirsch and Han, 1969 ; Johnston et al , 1977 ; Ferrezuelo et al , 2012 ; Leitao and Kellogg, 2017 ). In budding yeast, the TORC2 network is required for these proportional relationships ( Lucena et al , 2018 ; Leitao et al , 2019 ). TORC2 signaling is high in rich carbon and low in poor carbon.…”

“…A key component of the TORC2 network is Rts1, a conserved regulatory subunit for protein phosphatase 2A. Loss of Rts1 causes a failure in nutrient modulation of cell size, as well as defects in nutrient modulation of TORC2 signaling ( Artiles et al , 2009 ; Lucena et al , 2018 ; Leitao et al , 2019 ). Therefore, to identify new components of the TORC2 network, we searched for targets of PP2A Rts1 .…”