A slowly cleaved viral signal peptide acts as a protein-integral immune evasion domain

Stress can induce cell surface expression of MHC-like ligands, including MICA, that activate NK cells. Human cytomegalovirus (HCMV) glycoprotein US9 downregulates the activating immune ligand MICA*008 to avoid NK cell activation, but the underlying mechanism remains unclear. Here, we show that the N-terminal signal peptide is the major US9 functional domain targeting MICA*008 to proteasomal degradation. The US9 signal peptide is cleaved with unusually slow kinetics and this transiently retained signal peptide arrests MICA*008 maturation in the endoplasmic reticulum (ER), and indirectly induces its degradation via the ER quality control system and the SEL1L-HRD1 complex. We further identify an accessory, signal peptide-independent US9 mechanism that directly binds MICA*008 and SEL1L. Collectively, we describe a dual-targeting immunoevasin, demonstrating that signal peptides can function as protein-integral effector domains.

Binding of Event Files in a (go/no-go) Simon Task With an Accessory Peripheral Signal

To understand the relation between the Simon effect and the time course of relevant and irrelevant code activations, we presented the response signal before or simultaneously with a go/no-go signal in an accessory Simon task. A peripheral accessory signal could appear before, simultaneously with or after the go/no-go signal. We observed a Simon effect when the accessory signal was presented just before or simultaneously with the go signal, irrespective of the delay between response and go/no-go signal. The Simon effect reversed when the accessory signal was presented 150 ms after the go signal when response information was presented first and the participants had to make a go/no-go decision afterwards or when they had to select a response when the go signal appeared. The reversal did not occur when both decisions were required at the same time. Our data suggest that the integration and release of event files are involved in the occurrence of the reversal. Response activation induced by the accessory stimulus facilitates/interferes with the response when it is presented before the event file is integrated. When the accessory stimulus is presented after integration, the automatically activated response is inhibited, causing a delay in the corresponding reaction times.