Trivalent arsenic inhibits the functions of chaperonin complex.
The exact molecular mechanisms by which the environmental pollutant arsenic works in biological systems are not completely understood. Using an unbiased chemogenomics approach in Saccharomyces cerevisiae, we found that mutants of the chaperonin complex TRiC and the functionally related prefoldin complex are all hypersensitive to arsenic compared to a wild-type strain. In contrast, mutants with impaired ribosome functions were highly arsenic resistant. These observations led us to hypothesize that arsenic might inhibit TRiC function, required for folding of actin, tubulin, and other proteins postsynthesis. Consistent with this hypothesis, we found that arsenic treatment distorted morphology of both actin and microtubule filaments. Moreover, arsenic impaired substrate folding by both bovine and archaeal TRiC complexes in vitro. These results together indicate that TRiC is a conserved target of arsenic inhibition in various biological systems.
Pan
Xuewen
X
Department of Biology and Integrated Imaging Center, The Johns Hopkins University, Baltimore, MD 21218, USA. xuewenp@bcm.tmc.edu
Reissman
Stefanie
S
Douglas
Nick R
NR
Huang
Zhiwei
Z
Yuan
Daniel S
DS
Wang
Xiaoling
X
McCaffery
J Michael
JM
Frydman
Judith
J
Boeke
Jef D
JD
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015153:Blotting, Western; D056404:Chaperonin Containing TCP-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D017017:Methanococcus / Q000187:drug effects; D008868:Microtubule Proteins; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000737:chemistry; D009154:Mutation; D010087:Oxides / Q000633:toxicity*; D017510:Protein Folding; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism
D000199:Actins; D001152:Arsenicals; D008868:Microtubule Proteins; D018832:Molecular Chaperones; D010087:Oxides; D029701:Saccharomyces cerevisiae Proteins; D014404:Tubulin; C112806:prefoldin; D056404:Chaperonin Containing TCP-1; D000077237:Arsenic Trioxide