期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 28, 期 17, 页码 5223-5237出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00431-08
关键词
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资金
- NIH [P01 AI057596, R01 AI059465, T32 AI00743]
- Integrative Graduate Education and Research Traineeship [DGE0333196]
- NSF
- Initiative for Minority Students [R25 GM058389]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [Z01AI000743, R01AI059465, P01AI057596] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R25GM058389] Funding Source: NIH RePORTER
Controlled, transient cytokine production by monocytes depends heavily upon rapid mRNA degradation, conferred by 3' untranslated region-localized AU-rich elements (AREs) that associate with RNA-binding proteins. The ARE-binding protein AUF1 forms a complex with cap-dependent translation initiation factors and heat shock proteins to attract the mRNA degradation machinery. We refer to this protein assembly as the AUF1- and signal transduction-regulated complex, ASTRC. Rapid degradation of ARE-bearing mRNAs (ARE-mRNAs) requires ubiquitination of AUF1 and its destruction by proteasomes. Activation of monocytes by adhesion to capillary endothelium at sites of tissue damage and subsequent proinflammatory cytokine induction are prominent features of inflammation, and ARE-mRNA stabilization plays a critical role in the induction process. Here, we demonstrate activation-induced subunit rearrangements within ASTRC and identify chaperone Hsp27 as a novel subunit that is itself an ARE-binding protein essential for rapid ARE-mRNA degradation. As Hsp27 has well-characterized roles in protein ubiquitination as well as in adhesion-induced cytoskeletal remodeling and cell motility, its association with ASTRC may provide a sensing mechanism to couple proinflammatory cytokine induction with monocyte adhesion and motility.
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