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Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L).

ABSTRACT: Heat shock factor Hsf1 is involved in the regulation of a variety of cellular processes including heat shock response, development and differentiation, aging, and tumorigenesis. Hsf1 transcriptional activity is tightly controlled through phosphorylation, sumoylation, and acetylation, and through association with a number of regulatory proteins. However, regulation of Hsf1 protein stability or turnover remains unknown. We have identified a novel Hsf1-interacting protein, FILIP-1L, that was found to bind to Hsf1 through yeast two-hybrid screening. FILIP-1L encodes multiple isoforms spanning from 711 to 1135 amino acid residues. FILIP-1L contains four coiled-coil and two N-terminal leucine zipper domains. Ectopic expression of FILIP-1L reduces the expression of the Hsf1 protein because FILIP-1L promotes Hsf1 ubiquitination and degradation through the ubiquitin-proteasome system, leading to a reduction in Hsf1-mediated transcription. FILIP-1L, Hsf1, and the ubiquitin-binding domain of HhR23A, a receptor that transports polyubiquitinated proteins to the 19 S proteasome subunit targeting them for degradation, are found in a complex. This indicates that FILIP-1L is a potential adaptor that is involved in the Hsf1 degradation pathway. Taken together, our results indicate that FILIP-1L interacts with Hsf1, controlling its stability and thus modulating the heat shock response. These data indicate a novel function for FILIP-1L and a pathway for Hsf1 degradation through the ubiquitin-proteasome system.

SUBMITTER: Hu Y

PROVIDER: S-EPMC3173115 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L).

Hu Yanzhong Y Mivechi Nahid F NF

The Journal of biological chemistry 20110722 36

Heat shock factor Hsf1 is involved in the regulation of a variety of cellular processes including heat shock response, development and differentiation, aging, and tumorigenesis. Hsf1 transcriptional activity is tightly controlled through phosphorylation, sumoylation, and acetylation, and through association with a number of regulatory proteins. However, regulation of Hsf1 protein stability or turnover remains unknown. We have identified a novel Hsf1-interacting protein, FILIP-1L, that was found ...[more]

PMID: 21784850

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Project description:We showed that nitric oxide (NO) signaling is decreased in the pulmonary vasculature before the development of endothelial dysfunction in a lamb model of congenital heart disease and increased pulmonary blood flow (Shunt). The elucidation of the molecular mechanism by which this occurs was the purpose of this study. Here, we demonstrate that concentrations of the endogenous NO synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), are elevated, whereas the NOS cofactor tetrahydrobiopterin (BH(4)) is decreased in Shunt lambs. Our previous studies demonstrated that ADMA decreases heat shock protein-90 (Hsp90) chaperone activity, whereas other studies suggest that guanosine-5'-triphosphate cyclohydrolase 1 (GCH1), the rate-limiting enzyme in the generation of BH(4), may be a client protein for Hsp90. Thus, we determined whether increases in ADMA could alter GCH1 protein and activity. Our data demonstrate that ADMA decreased GCH1 protein, but not mRNA concentrations, in pulmonary arterial endothelial cells (PAECs) because of the ubiquitination and proteasome-dependent degradation of GCH1. We also found that Hsp90-GCH1 interactions were reduced, whereas the association of GCH1 with Hsp70 and the C-terminus of Hsp70-interacting protein (CHIP) increased in ADMA-exposed PAECs. The overexpression of CHIP potentiated, whereas a CHIP U-box domain mutant attenuated, ADMA-induced GCH1 degradation and reductions in cellular BH(4) concentrations. We also found in vivo that Hsp90/GCH1 interactions are decreased, whereas GCH1-Hsp70 and GCH1-CHIP interactions and GCH1 ubiquitination are increased. Finally, we found that supplementation with l-arginine restored Hsp90-GCH1 interactions and increased both BH(4) and NO(x) concentrations in Shunt lambs. In conclusion, increased concentrations of ADMA can indirectly alter NO signaling through decreased cellular BH(4) concentrations, secondary to the disruption of Hsp90-GCH1 interactions and the CHIP-dependent proteasomal degradation of GCH1.

Dataset Information

Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L).

Publications

Promotion of heat shock factor Hsf1 degradation via adaptor protein filamin A-interacting protein 1-like (FILIP-1L).

Similar Datasets

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