Nicholson-Projects

Nicholson-Projects

Researcher: 
Professor Sandra Nicholson

Projects

Last modified: 
Wed, 21/12/2022 - 12:02pm

SOCS proteins in Inflammation

Cytokine signalling is initiated through interaction with specific transmembrane receptor subunits. The subsequent receptor oligomerisation activates either an intrinsic kinase domain or the receptor associated JAK kinases, and the following cascade of intracellular phosphorylation and signal transduction culminates in an appropriate cellular response. This cascade requires exquisite cellular control, and loss of regulation can promote tumorigenesis and chronic inflammation. The expression of SOCS proteins can be induced by cytokine stimulation, and they serve to interfere with signalling not only from the inducing cytokine in a classic “negative-feedback” loop, but also to regulate signalling downstream of other cytokines.

Regulating anti-viral immunity

Many TRIM (tripartite motif) proteins are involved in anti-viral defence, innate immunity and inflammation. The B30.2 or PRYSPRY domain is a modular protein interaction domain found in TRIM proteins including TRIM5alpha, which controls HIV infection, TRIM20, which is mutated in familial Mediterranean fever and TRIM25, which regulates the viral RNA sensor RIG-I. We are interested in understanding how the B30.2-containing TRIM proteins recognize their cellular targets, and particularly how TRIM25 interacts with and activates RIG-I. This may lead to the development of new drugs that can either decrease inflammation to prevent chronic disease, or trigger the innate immune system to fight infection.

SPRY and SOCS box proteins in inflammation

The SPSB protein family is characterized by a central SPRY protein-interaction domain and a C-terminal SOCS box motif. The SOCS box motif recruits an E3 ubiquitin ligase complex, which polyubiquitinates target proteins, resulting in their proteasomal degradation. The number of proteins encoding SPRY domains now exceeds 74. These proteins are implicated in diverse biological processes including development and innate immunity.

We are interested in identifying potential binding partners for the SPSB proteins, and how the SPRY domain interacts with its target proteins. We have obtained detailed structural information on the binding interface between SPSB SPRY domains and the N-terminus of iNOS, and we are now interested in identifying lead compounds to disrupt this interaction.

Collaboration: Professor Ray Norton, Monash Institute of Pharmaceutical Sciences