CHIP activates HSF1 and confers protection against apoptosis and cellular stress

Abstract

contributed equally to this work Induction of molecular chaperones is the characteristic protective response to environmental stress, and is regulated by a transcriptional program that depends on heat shock factor 1 (HSF1), which is normally under negative regulatory control by molecular chaperones Hsp70 and Hsp90. In metazoan species, the chaperone system also provides protection against apoptosis. We demonstrate that the dual function cochaperone/ubiquitin ligase CHIP (C-terminus of Hsp70-interacting protein) regulates activation of the stress-chaperone response through induced trimerization and transcriptional activation of HSF1, and is required for protection against stress-induced apoptosis in murine ®broblasts. The consequences of this function are demonstrated by the phenotype of mice lacking CHIP, which develop normally but are temperature-sensitive and develop apoptosis in multiple organs after environmental challenge. CHIP exerts a central and unique role in tuning the response to stress at multiple levels by regulation of protein quality control and transcriptional activation of stress response signaling.

Nuclear FAK: a New Mode of Gene Regulation from Cellular Adhesions

“…FAK inhibition prevents inflammatory VCAM-1 expression which plays a critical role in recruiting leukocytes via its α4 integrin to the inflamed sites to enhance inflammation responses (Carter and Wicks, 2001;Cybulsky et al, 2001;. Interestingly, FAK inhibition in MEFs and ECs also promotes FAK accumulation in the nucleus and facilitates the FERM domain-mediated turnover of transcription factor GATA4 which is essential for VCAM-1 expression by recruiting ubiquitin E3 ligase CHIP (C-terminus Hsp70 interacting protein) (Ahmad et al, 1998;Dai et al, 2003;Kobayashi et al, 2007;Minami and Aird, 2001;Molkentin, 2000). FAK-GATA4 regulation is similar to that of FAK-p53, suggesting that nuclear FAK FERM is indeed a scaffold facilitating the turnover of transcription factors.…”

Chaperone-assisted degradation: multiple paths to destruction

“…It remains to be determined, however, whether the observed phenotype is indeed caused by impaired CAP. CHIP fulfils a degradation-independent function in the heat shock response by regulating the interaction of the heat shock transcription factor HSF-1 with Hsp90 (Dai et al, 2003). The lack of the co-chaperone could therefore broadly affect the ability of the organism to cope with protein misfolding.…”

Brain distribution of carboxy terminus of Hsc70-interacting protein (CHIP) and its nuclear translocation in cultured cortical neurons following heat stress or oxygen–glucose deprivation

“…CHIP (-/-) mice and cells cultured from these mice undergo temperature-sensitive apoptosis in response to thermal and proteotoxic stress (Dai et al 2003). CHIP (-/-) mice subjected to a model of cardiac ischemia and reperfusion had larger infarcts and increased rates of arrhythmia and mortality when compared with wild-type littermates .…”

“…CHIP has also been shown to stabilize HSF1 in its active form, which binds to and activates promoter regions of stress response genes (Dai et al 2003;Kim et al 2005). Overexpression of CHIP leads to upregulation of several chaperone proteins, especially and most profoundly HSP70.…”