New Regulators of a High Affinity Ca2+ Influx System Revealed through a Genome-wide Screen in Yeast

被引:80
作者
Martin, D. Christian [1 ]
Kim, Hyemin
Mackin, Nancy A. [3 ]
Maldonado-Baez, Lymarie [1 ]
Evangelista, Carlos C., Jr. [1 ]
Beaudry, Veronica G. [1 ]
Dudgeon, Drew D. [1 ]
Naiman, Daniel Q. [2 ]
Erdman, Scott E. [3 ]
Cunningham, Kyle W. [1 ]
机构
[1] Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA
[2] Johns Hopkins Univ, Dept Appl Math & Stat, Baltimore, MD 21218 USA
[3] Syracuse Univ, Dept Biol, Syracuse, NY 13244 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
ENDOPLASMIC-RETICULUM STRESS; GPI-ANCHORED PROTEINS; SACCHAROMYCES-CEREVISIAE; BIOACTIVE COMPOUNDS; INTERACTION NETWORK; MEMBRANE-PROTEINS; CALCIUM-CHANNEL; GENE-EXPRESSION; CALCINEURIN; HOMOLOG;
D O I
10.1074/jbc.M110.177451
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The bakers' yeast Saccharomyces cerevisiae utilizes a high affinity Ca2+ influx system (HACS) to survive assaults by mating pheromones, tunicamycin, and azole-class antifungal agents. HACS consists of two known subunits, Cch1 and Mid1, that are homologous and analogous to the catalytic alpha-subunits and regulatory alpha 2 delta-subunits of mammalian voltage-gated calcium channels, respectively. To search for additional subunits and regulators of HACS, a collection of gene knock-out mutants was screened for abnormal uptake of Ca2+ after exposure to mating pheromone or to tunicamycin. The screen revealed that Ecm7 is required for HACS function in most conditions. Cycloheximide chase experiments showed that Ecm7 was stabilized by Mid1, and Mid1 was stabilized by Cch1 in non-signaling conditions, suggesting they all interact. Ecm7 is a member of the PMP-22/EMP/MP20/Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels. Eleven additional members of this superfamily were identified in yeast, but none was required for HACS activity in response to the stimuli. Remarkably, many dozens of genes involved in vesicle-mediated trafficking and protein secretion were required to prevent spontaneous activation of HACS. Taken together, the findings suggest that HACS and calcineurin monitor performance of the membrane trafficking system in yeasts and coordinate compensatory processes. Conservation of this quality control system in Candida glabrata suggests that many pathogenic species of fungi may utilize HACS and calcineurin to resist azoles and other compounds that target membrane biosynthesis.
引用
收藏
页码:10744 / 10754
页数:11
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