Unified mechanisms for self-RNA recognition by RIG-I Singleton-Merten syndrome variants.

The innate immune sensor retinoic acid-inducible gene I (RIG-I) detects cytosolic viral RNA and requires a conformational change caused by both ATP and RNA binding to induce an active signaling state and to trigger an immune response. Previously, we showed that ATP hydrolysis removes RIG-I from lower-affinity self-RNAs (Lässig et al., 2015), revealing how ATP turnover helps RIG-I distinguish viral from self-RNA and explaining why a mutation in a motif that slows down ATP hydrolysis causes the autoimmune disease Singleton-Merten syndrome (SMS). Here we show that a different, mechanistically unexplained SMS variant, C268F, which is localized in the ATP-binding P-loop, can signal independently of ATP but is still dependent on RNA. The structure of RIG-I C268F in complex with double-stranded RNA reveals that C268F helps induce a structural conformation in RIG-I that is similar to that induced by ATP. Our results uncover an unexpected mechanism to explain how a mutation in a P-loop ATPase can induce a gain-of-function ATP state in the absence of ATP.

The radiographic stage of giant cell tumor related to stromal cells' proliferation. Tissue cultures in 13 cases.

The clinical behavior of giant cell tumor is related to the radiological appearance. To test the hypothesis that in vitro proliferation of the neoplastic stromal cell population of giant cell tumors is related to the radiological appearance, this study was undertaken. A prospective analysis of the cells migrating from 13 consecutive tumors was conducted. Growth curves and population doubling-times (PDT) for first and fifth passages were calculated and alkaline phosphatase levels were measured and compared to preoperative radiographic staging. A strong negative correlation was found between PDT and the radiographic stage. Tumors in stages I and II (low aggressiveness) were found to have an average cell population doubling-time of 11 (SD 2.2) days, while those in stage III (high aggressiveness) showed a doubling-time of 6 (SD 2.2) days. Low alkaline phosphatase activity was noted in all cultures, a finding consistent with the putative preosteoblastic potential of these stromal cells. This putative origin is also indicated by the differentiation response to retinoic acid. The findings suggest that the in vitro proliferation of the mononuclear stromal cell population of giant cell tumors is related to the radiographic stage and may predict the clinical behavior of these tumors.