Suppressor of cytokine signaling 1 (SOCS1) limits NFκB signaling by decreasing p65 stability within the cell nucleus

Abstract

Suppressor of cytokine signaling (SOCS) proteins are inhibitors of cytoplasmic Janus kinases (Jak) and signal transducer and activator of transcription (STAT) signaling pathways. Previously the authors surprisingly observed that SOCS1 translocated into the nucleus, which was because of the presence of a nuclear localization sequence. This report now hypothesizes that SOCS1 mediates specific functions within the nuclear compartment because it is instantly transported into the nucleus, as shown by photoactivation and live cell imaging in human HEK293 cells. The NFκB component p65 is identified as an interaction partner for SOCS1 but not for other members of the SOCS family. SOCS1 bound to p65 only within the nucleus. By means of its SOCS box domain, SOCS1 operated as a ubiquitin ligase, leading to polyubiquitination and proteasomal degradation of nuclear p65. Thus, SOCS1 limited prolonged p65 signaling and terminated expression of NFκB inducible genes. Using mutants that lack either nuclear translocation or a functional SOCS box, this report identifies genes that are regulated in a manner dependent on the nuclear availability of SOCS1. Data show that beyond its receptor-proximal function in Jak/STAT signaling, SOCS1 also regulates the duration of NFκB signaling within the cell nucleus, thus exerting a heretofore unrecognized function.

Suppressors of Cytokine Signaling Promote Fas-Induced Apoptosis through Downregulation of NF-κB and Mitochondrial Bfl-1 in Leukemic T Cells

“…Whereas these preceding studies suggest the mechanism of SOCS1 action in suppressing nuclear NF-kB activity and the target gene expression at the molecular level, our work presents a complete system where such inhibitory action of SOCS on the NF-kB activation via expression of specific gene products translates into the regulation of cell survival response against apoptotic stimuli in a defined cell type. Strebovsky et al (32) reported a lack of SOCS3 regulation of p65 in their experimental system. We have, however, shown in human leukemic Jurkat T cells that SOCS3 also acted as a potent proapoptotic factor during the Fas-induced cell death with suppressive effects on NF-kB activation and Bfl-1 expression.…”

“…Our data further show that SOCS1 coimmunoprecipitates p65 as well as p50, suggesting the molecular interaction of SOCS1 with the NF-kB complex of p65/p50. Of note, while this manuscript was in preparation, SOCS1 action to limit the duration NF-kB signaling through SOCS box-mediated p65 degradation in the nucleus was reported using kB-dependent reporter gene assays in SOCS1-transfected HEK 293 cells (32). Whereas these preceding studies suggest the mechanism of SOCS1 action in suppressing nuclear NF-kB activity and the target gene expression at the molecular level, our work presents a complete system where such inhibitory action of SOCS on the NF-kB activation via expression of specific gene products translates into the regulation of cell survival response against apoptotic stimuli in a defined cell type.…”

“…In this regard, SOCS1 has been shown to interact with Tel-Jak2, IRS-2, and Vav, leading to the target protein degradation via ubiquitination machinery (28)(29)(30). Additionally, SOCS1 has been proposed to control the transactivator function of NF-kB for suppression of NF-kB-responsive genes likely through the SOCS box-mediated p65 degradation (31,32).…”

Dectin-1 Stimulation Induces Suppressor of Cytokine Signaling 1, Thereby Modulating TLR Signaling and T Cell Responses

“…Because it was shown that SOCS1 contributes to ubiquitination and subsequent degradation of NF-kB (31,32), thereby modulating a subset of NF-kB-induced genes, we wanted to analyze whether activation of NF-kB transcription factors after costimulation with CpG-DNA and dZ was altered. We first tested whether the costimulation causes an increase in SOCS1 expression.…”

SOCS1 gene mutations in patients with diffuse large B-cell lymphoma

“…Известно, что белок SOCS1 взаимодействует с Toll-подобным рецептором (TLR), белками NF-κB и p53, за счет чего может играть роль в процессе подавления канцерогенеза [24][25][26][27]. Кроме того, SOCS1 может способствовать фосфорилированию р53 и его активации, что приводит к реализации зависимых от р53 процессов в активированной онкогенами клетке [28,29].…”