Generation of an inducible and reversible in vivo protein degradation system to study the role of the protein tyrosine phosphatase SHP-1 in T cell function 4719

Description Transgenic and knockout mouse models have significantly contributed to the progress on the in vivo understanding of molecules and pathways underlying human health. However, once a gene has been targeted, the genetic change is permanent. Approaches that specifically and reversibly target the protein rather than the gene, in the cell lineage of choice, would therefore be a great resource. Here, we generated an in vivo method that can achieve Inducible and Resersible In vivo Protein degradation (IRIP) by combining the power of two approaches: a recently described Auxin-induced degron (AID) system for reversible protein degradation and lineage-specific targeting via existing Cre-lines. Specifically as a proof of principle, we engineered a mouse model to achieve T cell-specific IRIP of SHP-1 by generating and combining two novel mouse strains; (1) a strain that expresses the Auxin-responsive TIR1 protein in a Cre-dependent manner allowing for cell lineage-specific expression using existing Cre strains, and (2) a strain that tags endogenous SHP-1 with an AID-targeting sequence. Functional assays have demonstrated the specificity of the AID system in vivo allowing for new insights into the role of SHP-1 during an immune response. Moreover, we believe that the development of this murine model of inducible and reversible protein degradation (IRIP) created a new tool for in vivo studies with significant benefit for the larger research community.