Changes in Cell Morphology Are Coordinated with Cell Growth through the TORC1 Pathway

BACKGROUND Growth rate is determined not only by extracellular cues such as nutrient availability but also by intracellular processes. Changes in cell morphology in budding yeast, mediated by polarization of the actin cytoskeleton, have been shown to reduce cell growth. RESULTS Here we demonstrate that polarization of the actin cytoskeleton inhibits the highly conserved Target of Rapamycin Complex 1 (TORC1) pathway. This downregulation is suppressed by inactivation of the TORC1 pathway regulatory Iml1 complex, which also regulates TORC1 during nitrogen starvation. We further demonstrate that attenuation of growth is important for cell recovery after conditions of prolonged polarized growth. CONCLUSIONS Our results indicate that extended periods of polarized growth inhibit protein synthesis, mass accumulation, and the increase in cell size at least in part through inhibiting the TORC1 pathway. We speculate that this mechanism serves to coordinate the ability of cells to increase in size with their biosynthetic capacity.

[1]  Daniel P. Haeusser,et al.  The great divide: coordinating cell cycle events during bacterial growth and division. , 2008, Current opinion in microbiology.

[2]  Mike Tyers,et al.  How Cells Coordinate Growth and Division , 2004, Current Biology.

[3]  M. Kirschner,et al.  Cell Growth and Size Homeostasis in Proliferating Animal Cells , 2009, Science.

[4]  K. Arndt,et al.  TIP41 interacts with TAP42 and negatively regulates the TOR signaling pathway. , 2001, Molecular cell.

[5]  J. Mitchison,et al.  The growth of single cells. I. Schizosaccharomyces pombe. , 1957, Experimental cell research.

[6]  T. Maeda,et al.  Transient sequestration of TORC1 into stress granules during heat stress. , 2012, Molecular cell.

[7]  D. Botstein,et al.  Ultrastructure of the yeast actin cytoskeleton and its association with the plasma membrane , 1994, The Journal of cell biology.

[8]  Michael N. Hall,et al.  The Rapamycin-sensitive Phosphoproteome Reveals That TOR Controls Protein Kinase A Toward Some But Not All Substrates , 2010, Molecular biology of the cell.

[9]  J. Yates,et al.  Npr2, Yeast Homolog of the Human Tumor Suppressor NPRL2, Is a Target of Grr1 Required for Adaptation to Growth on Diverse Nitrogen Sources , 2010, Eukaryotic Cell.

[10]  Michael N. Hall,et al.  The TOR signalling pathway controls nuclear localization of nutrient-regulated transcription factors , 1999, Nature.

[11]  Ronald W. Davis,et al.  A Genome-Wide Screen for Regulators of TORC1 in Response to Amino Acid Starvation Reveals a Conserved Npr2/3 Complex , 2009, PLoS genetics.

[12]  Gonghong Yan,et al.  The TOR complex 1 is a direct target of Rho1 GTPase. , 2012, Molecular cell.

[13]  Mike Tyers,et al.  Systematic Identification of Pathways That Couple Cell Growth and Division in Yeast , 2002, Science.

[14]  D. Koller,et al.  Sfp1 is a stress- and nutrient-sensitive regulator of ribosomal protein gene expression. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  M. Tyers,et al.  The cyclin-dependent kinase inhibitor p40SIC1 imposes the requirement for Cln G1 cyclin function at Start. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[16]  N. Oshiro,et al.  Tor Directly Controls the Atg1 Kinase Complex To Regulate Autophagy , 2009, Molecular and Cellular Biology.

[17]  K. Arndt,et al.  Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. , 1996, Genes & development.

[18]  Peter G. Schultz,et al.  A chemical switch for inhibitor-sensitive alleles of any protein kinase , 2000, Nature.

[19]  M. Tyers,et al.  The rate of cell growth is governed by cell cycle stage. , 2009, Genes & development.

[20]  S. Reed,et al.  Morphogenesis in the yeast cell cycle: regulation by Cdc28 and cyclins , 1993, The Journal of cell biology.

[21]  C. Kaiser,et al.  A conserved GTPase-containing complex is required for intracellular sorting of the general amino-acid permease in yeast , 2006, Nature Cell Biology.

[22]  N. Baba,et al.  Three-dimensional analysis of morphogenesis induced by mating pheromone alpha factor in Saccharomyces cerevisiae. , 1989, Journal of cell science.

[23]  C. De Virgilio,et al.  Leucyl-tRNA synthetase controls TORC1 via the EGO complex. , 2012, Molecular cell.

[24]  L. Hartwell Periodic Density Fluctuation During the Yeast Cell Cycle and the Selection of Synchronous Cultures , 1970, Journal of bacteriology.

[25]  S. Manalis,et al.  Weighing of biomolecules, single cells and single nanoparticles in fluid , 2007, Nature.

[26]  J. Warner,et al.  Synthesis of ribosomal proteins during the cell cycle of the yeast Saccharomyces cerevisiae , 1979, Journal of bacteriology.

[27]  C. Woldringh,et al.  Volume growth of daughter and parent cells during the cell cycle of Saccharomyces cerevisiae a/alpha as determined by image cytometry , 1993, Journal of bacteriology.

[28]  M. Tyers,et al.  A dynamic transcriptional network communicates growth potential to ribosome synthesis and critical cell size. , 2004, Genes & development.

[29]  James R Broach,et al.  How Saccharomyces responds to nutrients. , 2008, Annual review of genetics.

[30]  M. Tyers,et al.  A Rab escort protein integrates the secretion system with TOR signaling and ribosome biogenesis. , 2009, Genes & development.

[31]  J. Boeke,et al.  Efficient Tor Signaling Requires a Functional Class C Vps Protein Complex in Saccharomyces cerevisiae , 2007, Genetics.

[32]  Cahir J. O'Kane,et al.  Lysosomal positioning coordinates cellular nutrient responses , 2011, Nature Cell Biology.

[33]  References , 1971 .

[34]  A. Bretscher,et al.  Mechanisms of polarized growth and organelle segregation in yeast. , 2004, Annual review of cell and developmental biology.

[35]  Robbie Loewith,et al.  Sch9 is a major target of TORC1 in Saccharomyces cerevisiae. , 2007, Molecular cell.

[36]  J. Mitchison The growth of single cells. II. Saccharomyces cerevisiae. , 1958, Experimental cell research.

[37]  Frederick R. Cross,et al.  The effects of molecular noise and size control on variability in the budding yeast cell cycle , 2007, Nature.

[38]  M. Wigler,et al.  Genetic analysis of yeast RAS1 and RAS2 genes , 1984, Cell.

[39]  P. Sharp,et al.  14-3-3σ controls mitotic translation to facilitate cytokinesis , 2007, Nature.

[40]  J. Thorner,et al.  Yeast mating pheromone alpha factor inhibits adenylate cyclase. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Crespo,et al.  The TOR-controlled transcription activators GLN3, RTG1, and RTG3 are regulated in response to intracellular levels of glutamine , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Philippsen,et al.  Additional modules for versatile and economical PCR‐based gene deletion and modification in Saccharomyces cerevisiae , 1998, Yeast.

[43]  P. Nurse,et al.  Growth in cell length in the fission yeast Schizosaccharomyces pombe. , 1985, Journal of cell science.

[44]  Andrea K. Bryan,et al.  Measurement of mass, density, and volume during the cell cycle of yeast , 2009, Proceedings of the National Academy of Sciences.

[45]  K. Mizuta,et al.  Continued functioning of the secretory pathway is essential for ribosome synthesis , 1994, Molecular and cellular biology.

[46]  Samara L. Reck-Peterson,et al.  Role of actin and Myo2p in polarized secretion and growth of Saccharomyces cerevisiae. , 2000, Molecular biology of the cell.

[47]  Nicolas Panchaud,et al.  The Vam6 GEF controls TORC1 by activating the EGO complex. , 2009, Molecular cell.

[48]  Ruedi Aebersold,et al.  Characterization of the rapamycin-sensitive phosphoproteome reveals that Sch9 is a central coordinator of protein synthesis. , 2009, Genes & development.

[49]  M. Hall,et al.  Target of Rapamycin (TOR) in Nutrient Signaling and Growth Control , 2011, Genetics.

[50]  Avner Schlessinger,et al.  A Conserved Coatomer-related Complex Containing Sec13 and Seh1 Dynamically Associates With the Vacuole in Saccharomyces cerevisiae* , 2011, Molecular & Cellular Proteomics.

[51]  David M. Sabatini,et al.  The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1 , 2008, Science.

[52]  P. Sharp,et al.  14-3-3sigma controls mitotic translation to facilitate cytokinesis. , 2007, Nature.