title: Cdc48 and cofactors Npl4-Ufd1 are important for G1 progression during heat stress by maintaining cell wall integrity in Saccharomyces cerevisiae.
abstract: The ubiquitin-selective chaperone Cdc48, a member of the AAA (ATPase Associated with various cellular Activities) ATPase superfamily, is involved in many processes, including endoplasmic reticulum-associated degradation (ERAD), ubiquitin- and proteasome-mediated protein degradation, and mitosis. Although Cdc48 was originally isolated as a cell cycle mutant in the budding yeast Saccharomyces cerevisiae, its cell cycle functions have not been well appreciated. We found that temperature-sensitive cdc48-3 mutant is largely arrested at mitosis at 37°C, whereas the mutant is also delayed in G1 progression at 38.5°C. Reporter assays show that the promoter activity of G1 cyclin CLN1, but not CLN2, is reduced in cdc48-3 at 38.5°C. The cofactor npl4-1 and ufd1-2 mutants also exhibit G1 delay and reduced CLN1 promoter activity at 38.5°C, suggesting that Npl4-Ufd1 complex mediates the function of Cdc48 at G1. The G1 delay of cdc48-3 at 38.5°C is a consequence of cell wall defect that over-activates Mpk1, a MAPK family member important for cell wall integrity in response to stress conditions including heat shock. cdc48-3 is hypersensitive to cell wall perturbing agents and is synthetic-sick with mutations in the cell wall integrity signaling pathway. Our results suggest that the cell wall defect in cdc48-3 is exacerbated by heat shock, which sustains Mpk1 activity to block G1 progression. Thus, Cdc48-Npl4-Ufd1 is important for the maintenance of cell wall integrity in order for normal cell growth and division.
authors.affiliation: Molecular Cell Biology, Taiwan International Graduate Program, Institute of Molecular Biology, Academia Sinica, and National Defense Medical Center, Taipei, Taiwan.
authors.forename: Meng-Ti
authors.initials: MT
authors.lastname: Hsieh
authors.forename: Rey-Huei
authors.initials: RH
authors.lastname: Chen
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002473:Cell Wall / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D016193:G1 Phase; D018869:Heat-Shock Response; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism*; D009994:Osmolar Concentration; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D013696:Temperature; D000074405:Valosin Containing Protein; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; C104361:NPL4 protein, S cerevisiae; D029543:Nucleocytoplasmic Transport Proteins; D029701:Saccharomyces cerevisiae Proteins; C444652:UFD1 protein, S cerevisiae; D033921:Vesicular Transport Proteins; D000251:Adenosine Triphosphatases; C000614177:CDC48 protein, S cerevisiae; D000074405:Valosin Containing Protein