Abstract
Author SummaryStat3 is a multidomain transcription factor that contributes to many cellular functions by transmitting signals for over 40 peptide hormones from the cell surface to the nucleus. Understanding how multidomain proteins achieve their fully folded and functional state is of substantial biological interest. As Stat3 signaling is up-regulated in many pathological conditions, including cancer and inflammatory diseases, insight into what controls its folding may be useful for the identification of vulnerabilities that can be therapeutically exploited. We demonstrate that the major protein-folding machine or chaperonin within eukaryotic cells, TRiC/CCT, is required for Stat3 to fold during its synthesis and for Stat3 to be fully functional within the cell. We also find that TRiC can refold chemically denatured Stat3 and provide evidence that the CCT3 subunit of TRiC binds to the DNA-binding domain of Stat3. We also show that Stat3 activity is decreased by down-modulating levels of TRiC and can be increased by increasing Stat3's interaction with TRiC. TRiC therefore regulates both Stat3 protein levels and its function, making Stat3 modulation by manipulation of its interaction with TRiC a potential approach for the treatment of cancer and inflammatory diseases.
Highlights
Signal transducer and activator of transcription 3 (Stat3) is a member of a family of seven closely related proteins responsible for the transmission of peptide hormone signals from the extracellular surface of cells to the nucleus [1,2]
We demonstrate that the major protein-folding machine or chaperonin within eukaryotic cells, tailless complex protein-1 ring complex (TRiC)/chaperonin containing tailless complex protein-1 (TCP-1) (CCT), is required for Stat3 to fold during its synthesis and for Stat3 to be fully functional within the cell
We find that TRiC can refold chemically denatured Stat3 and provide evidence that the CCT3 subunit of TRiC binds to the DNA-binding domain of Stat3
Summary
Signal transducer and activator of transcription 3 (Stat3) is a member of a family of seven closely related proteins responsible for the transmission of peptide hormone signals from the extracellular surface of cells to the nucleus [1,2]. Conditional gene targeting of Stat in several types of tissues revealed important roles for Stat in key biological functions including cell survival and growth, immunity, and inflammation [3,4]. These findings in mice have been recapitulated, in part, in patients with autosomal-dominant hyper-IgE syndrome (AD-HIES) or Job’s syndrome, a rare immunodeficiency syndrome, which results from loss-of-function mutations in the Stat gene [5]. Despite its importance to normal physiology and pathophysiology, little is known about how Stat achieves its native state within the cell, information that potentially could be exploited to develop novel therapies for AD-HIES and/ or cancer
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