The immune sensitivity caused by DUSP11, an RNA 5'-end maturation phosphatase, is adjusted by a human non-coding RNA, nc886.

Abstract

All cellular transcripts initially have a tri-phosphate (PPP) group at the 5'-end, recognized as a pathogen-associated molecular pattern (PAMP) by a cell's innate immune system. The removal of 5'-PPP occurs to varying extents, causing immune imbalance. However, how cells manage this situation has not yet been documented. Among 5'-PPP removal mechanisms, recent attention has been towards an RNA phosphatase called Dual Specificity Phosphatase 11 (DUSP11), which acts preferentially on 5'-triphosphorylated (5'-PPP) RNAs transcribed by RNA polymerase III (Pol III) and converts them to a 5'-monophosphorylated (5'-P) form. Here we have elucidated that immune imbalance caused by variable DUSP11 expression in human is controlled by a Pol III-transcribed non-coding RNA (Pol III-ncRNA), nc886. DUSP11 depletion leads to the accumulation of 5'-PPP-Pol III-ncRNAs, making cells respond better to incoming PAMP. Distinctly from other Pol III-ncRNAs, DUSP11 depletion increases the expression of nc886 in a 5'-P form, which mitigates the sensitized immunity. nc886 expression is also increased by infection with Kaposi's sarcoma-associated herpesvirus (KSHV) that suppresses DUSP11, and, in turn, nc886 stimulates KSHV infectivity. DUSP11 levels in normal tissues are relatively constitutive in mice lacking nc886 but are variable in humans. This wide range of DUSP11 expression and the resultant immune imbalance is probably adjusted by nc886. In summary, our study of DUSP11 and nc886 has uncovered a novel mechanism by which human cells control immune sensitivity, which is intrinsically caused by cellular RNA metabolism, allowing different states of equilibrium between immune status and gene expression.