UC San Diego

Major Histocompatibility Complex Class I (MHCI) proteins were first identified in the immune system but are also expressed in neurons and play a role in normal brain development and plasticity. However little is known about how, on a molecular level, MHCI modifies neuronal structure and function. Here we show that MHCI proteins interact with neuronal insulin receptors (IR) and are critical for their signaling. Dendritically expressed MHCI is closely apposed to axonally expressed IR in many brain regions, including hippocampus, and MHCI co- immunoprecipitates with IR from mouse hippocampal lysates. Unexpectedly, genetic reduction of cell surface MHCI in either [beta]2m-/-TAP-/- or Kb-/-Db-/- mice selectively alters antibody binding to an intracellular domain of the β-subunit of IR, which contains key tyrosine residues that are autophosphorylated following ligand binding. This loss of antibody binding can be rescued by co-culturing [beta]2m-/-TAP-/- neurons with wild-type neurons, suggesting MHCI and IR can interact in trans. Furthermore, [beta]2m-/-TAP-/- mice show an increase in basal tyrosine phosphorylation of IR. This increase in basal activation of IR correlates with an increase in synapse density in MHCI-deficient animals specifically in regions where IR are expressed. Together our results demonstrate that endogenous MHCI is a novel regulator of neuronal IR function and synapse number, and suggest that MHCI modifies a key c-terminal signaling domain of IR in neurons