Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation.
Polarized cell motility induces hydrogen peroxide to inhibit cofilin via cysteine oxidation.
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DOI：
10.1016/j.cub.2015.04.020
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发表时间：
2015-06-01
期刊：
影响因子：
9.2
通讯作者：
Olson, Michael F.
中科院分区：
文献类型：
--
作者：
Cameron, Jenifer M.;Gabrielsen, Mads;Chim, Ya Hua;Munro, June;McGhee, Ewan J.;Sumpton, David;Eaton, Philip;Anderson, Kurt I.;Yin, Huabing;Olson, Michael F.
Mesenchymal cell motility is driven by polarized actin polymerization. Signals at the leading edge recruit actin polymerization machinery to promote membrane protrusion, while matrix adhesion generates tractive force to propel forward movement. To work effectively, cell motility is regulated by a complex network of signaling events that affect protein activity and localization. H2O2 has an important role as a diffusible second messenger, and mediates its effects through oxidation of cysteine thiols. One cell activity influenced by H2O2 is motility. However, a lack of sensitive and H2O2-specific probes for measurements in live cells has not allowed for direct observation of H2O2 accumulation in migrating cells or protrusions. In addition, the identities of proteins oxidized by H2O2 that contribute to actin dynamics and cell motility have not been characterized. We now show, as determined by fluorescence lifetime imaging microscopy, that motile cells generate H2O2 at membranes and cell protrusions and that H2O2 inhibits cofilin activity through oxidation of cysteines 139 (C139) and 147 (C147). Molecular modeling suggests that C139 oxidation would sterically hinder actin association, while the increased negative charge of oxidized C147 would lead to electrostatic repulsion of the opposite negatively charged surface. Expression of oxidation-resistant cofilin impairs cell spreading, adhesion, and directional migration. These findings indicate that H2O2 production contributes to polarized cell motility through localized cofilin inhibition and that there are additional proteins oxidized during cell migration that might have similar roles. Cell migration leads to localized hydrogen peroxide generation Motility increases protein oxidation on cysteine residues Cofilin oxidation on Cys139 and Cys147 reduces actin binding and severing Oxidation of cofilin, and possibly additional proteins, influences cell motility Cell migration is regulated by signaling events that regulate protein activity. Here, Cameron et al. imaged highest H2O2 levels in motile cell protrusions, accompanied by cysteine oxidation of proteins, including actin-regulating cofilin. Cofilin oxidation reduced actin binding and severing, linking H2O2-generation with cytoskeleton dynamics.
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DOI：
10.1038/nrm2957
发表时间：
2010-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Taulet N;Delorme-Walker VD;DerMardirossian C
通讯作者：
DerMardirossian C
影响因子：
3.3
作者：
Vitriol EA;Wise AL;Berginski ME;Bamburg JR;Zheng JQ
通讯作者：
Zheng JQ
影响因子：
6.6
作者：
Maller, Claire;Schroeder, Ewald;Eaton, Philip
通讯作者：
Eaton, Philip
影响因子：
48
作者：
Wisniewski, Jacek R.;Zougman, Alexandre;Mann, Matthias
通讯作者：
Mann, Matthias