New functions of Suppressor of Cytokine Signalling-1 (SOCS1) dependent on its nuclear localization

• Applicant: Professor Dr. Alexander Dalpke
• Subject Area: Cell Biology ; Immunology
• Term: from 2009 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 112926915

This is a renewal application for a project entitled 'Identification of nuclear functions of Suppressor of Cytokine Signalling-1 (SOCS1)' that was funded previously from 2009-2012 by DFG (DA592/4-1). SOCS proteins are inducible, intracellular feedback inhibitors of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Despite the well-studied function of SOCS proteins in inhibition of membrane-proximal cytokine receptor signaling we have identified a nuclear localization signal within SOCS1 resulting in nuclear translocation of SOCS1. In the last funding period we were for the first time able to assign a function to nuclear SOCS1 which is the limitation of NFkappaB signaling by proteasomal degradation of p65. To further identify new functions of nuclear SOCS1 within primary immune cells we have now generated BAC transgenic mice that express a non-nuclear SOCS1 mutant (together with eGFP and luciferase reporters) that allow studying the importance of nuclear localization when backcrossed to SOCS1-/- mice. It is suggested to interrogate the nuclear function of SOCS1 in three areas: i) It is hypothesized that nuclear SOCS1 regulates a subset of IFN inducible genes via proteasome activity thereby contributing to termination of IFN signaling. Such a mode of action would add an entirely new aspect to the known mechanism by which SOCS1 regulates interferon (IFN) signaling and could serve as template for other JAK/STAT dependent signaling modules as well. ii) It is hypothesized that translocation of SOCS1 into the nucleus is a regulated event that depends on protein modifications within the molecule. iii) New interaction partners of nuclear SOCS1 will be identified in an unbiased proteomics approach. Based on previous work the interplay of nuclear SOCS1 with candidate DDB1 and its role for cell cycle regulation will be studied first. From the experiments it is expected to gain new insight into hitherto ill-defined functions of nuclear SOCS1.

• DFG Programme: Research Grants