Slingshot-1 (SSH1) phosphatase Controls Cytoskeletal Remodeling, Integrin conformation and Metabolic Reprogramming During CD4 T Cell Activation

Effective T cell activation requires formation of the immunological synapse (IS), which depends on coordinated remodeling of actin and microtubule cytoskeletons. Upon T cell receptor (TCR) engagement, the phosphatase Slingshot-1 (SSH1) is rapidly recruited to the nascent IS, where it dephosphorylates cofilin and suppresses LIM kinase activity to promote actin dynamics. However, the mechanism by which SSH1 anchors at and controls IS formation is unknown. Here, we identify the role of SSH1 in assembling a protein hub with Talin-1, Kindlin-3, ADAP, and Myosin IIA that promotes high-affinity activation of the integrin LFA-1. This allows SSH1 to coordinately regulate actin and microtubule dynamics and ultimately facilitates the metabolic reprogramming of T cells. Loss of SSH1 disorganizes IS in terms of mitochondria, rewiring T cells toward fatty acid oxidation, congregating lipid droplets and peroxisomes, and preventing glucose metabolism. Together, our findings establish SSH1 as a node connecting cytoskeletal dynamics to metabolic adaptation for T cell activation.