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Heat shock protein 27 (HSP27) is a chaperone whose cellular expression increases in response to various stresses and protects the cell either by inhibiting apoptotic cell death or by promoting the ubiquitination and proteasomal degradation of specific proteins. Here, we show that globin transcription factor 1 (GATA-1) is a client protein of HSP27. In 2 models of erythroid differentiation; that is, in the human erythroleukemia cell line, K562 induced to differentiate into erythroid cells on hemin exposure and CD34 ؉ human cells ex vivo driven to erythroid differentiation in liquid culture, depletion of HSP27 provokes an accumulation of GATA-1 and impairs terminal maturation. More specifically, we demonstrate that, in the late stages of the erythroid differentiation program, HSP27 is phosphorylated in a p38-dependent manner, enters the nucleus, binds to GATA-1, and induces its ubiquitination and proteasomal degradation, provided that the transcription factor is acetylated. We conclude that HSP27 plays a role in the fine-tuning of terminal erythroid differentiation through regulation of GATA-1 content and activity. (Blood. 2010;116(1):85-96) IntroductionTerminal erythroid differentiation is driven by the glycoprotein hormone erythropoietin (Epo) and involves the sequential formation of proerythroblasts and basophilic, polychromatic, and orthochromatic erythroblasts in the bone marrow. This differentiation program is under control of the transcription factor GATA-1 (globin transcription factor 1), 1,2 which induces the expression of erythroid genes such as glycophorin A, Epo receptor, and hemoglobin. 3 GATA-1 also cooperates with Epo to promote erythroid precursor survival by positively regulating the bcl-x L gene. 3-5 On Epo starvation or engagement of the death receptor Fas (CD95/APO-1), caspases are activated and GATA-1 is cleaved. These events arrest erythroid precursor maturation and provoke cell death. 6,7 On Epo stimulation of erythroid precursors, caspase-3 is also transiently activated, and this activation is required for terminal erythroblast maturation, but GATA-1 remains uncleaved and erythroid cells do not die. [8][9][10] We have demonstrated that, in Epo-stimulated erythroid precursors, GATA-1 was protected from caspase-3-mediated cleavage by the stress-inducible heat shock protein 70 (HSP70). At the onset of caspase-3 activation, HSP70 translocates from the cytoplasm to the nucleus and interacts with GATA-1. Epo deprivation disrupts the GATA-1/HSP70 interaction and exposes GATA-1 to the proteolytic effect of caspase-3. 11 Another stress-inducible HSP that is expressed in erythroid cells undergoing differentiation is HSP27. 11 This small stress protein has shown prosurvival functions through interaction with proteins such as cytochrome c, caspase-3, death domainassociated protein, and actin (for a review, see Lanneau et al 12 ).HSP27 is also an adenosine triphosphate (ATP)-independent chaperone that binds ubiquitin, with a higher affinity for long chains of ubiquitin than for mono-ubiquitin, and orches...

La sensation douloureuse est une caractéristique de l’inflammation aiguë qui se développe lors d’une infection. Cette douleur s’estompe quelques jours après l’infection, lorsque les lymphocytes T effecteurs générés en réponse aux antigènes microbiens gagnent le site inflammatoire. Cette régulation de la douleur inflammatoire est tributaire de la libération locale d’opioïdes endogènes par les lymphocytes T et de leur action sur les nocicepteurs en périphérie. Ce phénomène pourrait expliquer pourquoi un certain nombre de patients atteints de maladies inflammatoires chroniques de l’intestin ne ressentent pas systématiquement des douleurs abdominales ou qu’elles ne font pas toujours partie du tableau clinique initial.