Post-translational regulation of the NKG2D ligand Mult1 in response to cell stess (134.2)

Abstract NKG2D is a major stimulatory receptor expressed by natural killer cells and some T cells. The receptor recognizes MHC class I-like cell surface ligands that are poorly expressed by normal tissues but often induced in transformed and infected cells. Induction of NKG2D ligands during transformation or infection leads to activation of NKG2D-expressing immune cells and elimination of the diseased target cells. The existence of several NKG2D ligands in each individual, some with strikingly divergent protein sequences, raises the possibility that different ligands are regulated by distinct disease-associated stresses. The transcripts for some ligands, including murine UL16-binding protein-like transcript 1 (Mult1), are abundant in certain normal tissues where cell surface expression is absent suggesting the existence of translational or post-translational regulation. We report that under normal conditions, Mult1 protein undergoes ubiquitination dependent on lysines in its cytoplasmic tail and is degraded by the lysosome. Mult1 degradation and ubiquitination is reduced in response to stress imparted by heat shock or ultraviolet (UV) irradiation, but not by other forms of genotoxicity, providing a novel mechanism for stress-mediated cellular control of NKG2D ligand expression.