The innate RNA sensor RIG-I is critical in the initiation of antiviral type I interferons (IFNs) production upon recognition of "non-self" viral RNAs. Here, we identify a host-derived, IFN-inducible long noncoding RNA, lnc-Lsm3b, that can compete with viral RNAs in the binding of RIG-I monomers and feedback inactivate the RIG-I innate function at late stage of innate response. Mechanistically, binding of lnc-Lsm3b restricts RIG-I protein's conformational shift and prevents downstream signaling, thereby terminating type I IFNs production. Multivalent structural motifs and long-stem structure are critical features of lnc-Lsm3b for RIG-I binding and inhibition. These data reveal a non-canonical self-recognition mode in the regulation of immune response and demonstrate an important role of an inducible "self" lncRNA acting as a potent molecular decoy actively saturating RIG-I binding sites to restrict the duration of "non-self" RNA-induced innate immune response and maintaining immune homeostasis, with potential utility in inflammatory disease management.
Long noncoding RNAs (lncRNAs) involved in the regulation of antiviral innate immune responses need to be further identified. By functionally screening the lncRNAs in macrophages, here we identified lncRNA Malat1, abundant in the nucleus but significantly down-regulated after viral infection, as a negative regulator of antiviral type I IFN (IFN-I) production. Malat1 directly bound to the transactive response DNA-binding protein (TDP43) in the nucleus and prevented activation of TDP43 by blocking the activated caspase-3-mediated TDP43 cleavage to TDP35. The cleaved TDP35 increased the nuclear IRF3 protein level by binding and degrading Rbck1 pre-mRNA to prevent IRF3 proteasomal degradation upon viral infection, thus selectively promoting antiviral IFN-I production. Deficiency of Malat1 enhanced antiviral innate responses in vivo, accompanying the increased IFN-I production and reduced viral burden. Importantly, the reduced MALAT1, augmented IRF3, and increased IFNA mRNA were found in peripheral blood mononuclear cells (PBMCs) from systemic lupus erythematosus (SLE) patients. Therefore, the down-regulation of MALAT1 in virus-infected cells or in human cells from autoimmune diseases will increase host resistance against viral infection or lead to autoinflammatory interferonopathies via the increased type I IFN production. Our results demonstrate that the nuclear Malat1 suppresses antiviral innate responses by targeting TDP43 activation via RNA-RBP interactive network, adding insight to the molecular regulation of innate responses and autoimmune pathogenesis.
The activation of retinoic acid-inducible gene 1 (RIG-I), a cytoplasmic innate sensor for viral RNA, is tightly regulated to maintain immune homeostasis properly and prevent excessive inflammatory reactions other than initiation of antiviral innate response to eliminate RNA virus effectively. Posttranslational modifications, particularly ubiquitination, are crucial for regulation of RIG-I activity. Increasing evidence suggests that E3 ligases play important roles in various cellular processes, including cell proliferation and antiviral innate signaling. Here we identify that E3 ubiquitin ligase RING finger protein 122 (RNF122) directly interacts with mouse RIG-I through MS screening of RIG-Iinteracting proteins in RNA virus-infected cells. The transmembrane domain of RNF122 associates with the caspase activation and recruitment domains (CARDs) of RIG-I; this interaction effectively triggers RING finger domain of RNF122 to deliver the Lys-48-linked ubiquitin to the Lys115 and Lys146 residues of RIG-I CARDs and promotes RIG-I degradation, resulting in a marked inhibition of RIG-I downstream signaling. RNF122 is widely expressed in various immune cells, with preferential expression in macrophages. Deficiency of RNF122 selectively increases RIG-I-triggered production of type I IFNs and proinflammatory cytokines in macrophages. RNF122-deficient mice exhibit more resistance against lethal RNA virus infection, with increased production of type I IFNs. Thus, we demonstrate that RNF122 acts as a selective negative regulator of RIG-I-triggered antiviral innate response by targeting CARDs of RIG-I and mediating proteasomal degradation of RIG-I. Our study outlines a way for E3 ligase to regulate innate sensor RIG-I for the control of antiviral innate immunity.RIG-I | E3 ligase | RNF122 | innate immunity | type I interferon
Background. Liposarcoma is a soft tissue malignancy, commonly observed in the extremities. However, retroperitoneal liposarcoma is seldom reported and its diagnosis is frequently neglected. This study aims to present the clinical characteristics, diagnosis, and prognosis of five liposarcoma subtypes and report our experience of patient treatment. Methods. We conducted a single-center noninterventional retrospective study of 57 retroperitoneal liposarcoma patients admitted to Peking Union Medical College Hospital (PUMCH, Beijing, China) between July 2011 and December 2019. We collected and analyzed their demographic, clinical, imaging, histological, therapeutic, and prognostic data over a mean 4.5-year follow-up period. Results. Twenty-five (44%) patients were asymptomatic prior to diagnosis, with abdominal distension as the chief complaint in 18 (32%) patients and abdominal pain observed in 16 (28%) patients. Masses were evaluated by computed tomography (n = 48, 84%) or ultrasound (n = 25, 44%). Laparotomy (n = 52, 91%) was the dominant therapeutic modality rather than laparoscopy (n = 5, 9%). All patients were treated with R0 resection except two patients who underwent R2 resection. We conducted regular follow-ups every six months after surgery for a mean duration of 4.5 years. Recurrence was experienced by 14 (25%) patients and a further 9 (16%) died during follow-up. Conclusions. Abdominal distension and pain are chief complaints with liposarcoma. As the extremities are the main liposarcomas locations, the diagnosis of retroperitoneal liposarcoma is usually neglected. Since half of the patients are asymptomatic, timely diagnosis and treatment are highly dependent on regular ultrasound and computed tomography imaging. R0 resection is the key to retroperitoneal liposarcoma treatment. In comparison, patients who underwent R2 resection, which is considered a palliative treatment, had bad prognoses. Large, symptomatic dedifferentiated, and pleomorphic liposarcomas are more likely to have poor prognoses, while the prognosis for well-differentiated or myxoid liposarcoma is relatively good.
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