Orientia tsutsugamushi Ank5 directs ubiquitination and proteasomal degradation of NLRC5 to inhibit major histocompatibility complex class I expression

How intracellular bacteria subvert the major histocompatibility complex (MHC) class I pathway is poorly understood. Here, we show that the obligate intracellular bacterium Orientia tsutsugamushi uses its effector protein, Ank5, to orchestrate proteasomal degradation of the MHC class I gene transactivator, NLRC5. Ank5 uses a tyrosine in its fourth ankyrin repeat to bind the NLRC5 N-terminus while its F-box directs host SCF complex ubiquitination of K1194 in the leucine-rich repeat region that dictates NLRC5 susceptibility to Orientia- and Ank5-mediated degradation. The ability of O. tsutsugamushi strains to degrade NLRC5 correlates with ank5 genomic carriage. Ectopically expressed Ank5 that can bind but not degrade NLRC5 protects the transactivator during Orientia infection. Thus, Ank5 is an immunoevasin that uses its bipartite architecture to rid host cells of NLRC5 and MHC class I molecules. This study offers insight into how intracellular pathogens can impair MHC class I expression to benefit their survival.