TRIM28 regulates SARS-CoV-2 cell entry by targeting ACE2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019, it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)- induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. The upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.

Autoantibody to transcriptional intermediary factor-1ß as a myositis-specific antibody: clinical correlation with clinically amyopathic dermatomyositis or dermatomyositis with mild myopathy.

BACKGROUND: Myositis-specific autoantibodies (MSAs) are associated with unique clinical subsets in polymyositis/dermatomyositis (PM/DM). Autoantibodies against transcriptional intermediary factor (TIF)-1γ and TIF-1α are known to be MSAs. Previously, we reported that TIF-1ß is also targeted in patients with DM with or without concomitant anti-TIF-1α/γ antibodies. OBJECTIVES: To evaluate the clinical features of seven cases with anti-TIF-1ß antibodies alone. METHODS: Serum autoantibody profiles were determined, and protein and RNA immunoprecipitation studies were conducted. Western blotting was performed to confirm autoantibody reactivity against TIF-1ß. RESULTS: Anti-TIF-1ß antibody was identified by immunoprecipitation assay in 24 cases. Among them, seven patients were positive for anti-TIF-1ß antibody alone. Six of the seven patients were classified as having DM. Among the six cases of DM, two patients had no muscle weakness and normal creatine kinase (CK) levels, and were classified as having clinically amyopathic DM. Four patients had muscle weakness, but three of them had normal serum CK levels that responded well to systemic steroids. Characteristic features of DM included skin rashes, such as Gottron sign, periungual erythema, punctate haemorrhage on the perionychium and facial erythema including heliotrope, which were observed in 86%, 57%, 86% and 71% of our cases, respectively. One of the seven patients had appendiceal cancer. None of the patients had interstitial lung disease. CONCLUSIONS: Seven patients were confirmed to have anti-TIF-1ß antibody without any other MSAs, including TIF-1α/γ antibodies, and six of them were diagnosed with DM. We suggest that anti-TIF-1ß antibody is an MSA, and that it is associated with clinically amyopathic DM or DM with mild myopathy.

Epigenetic activation during T helper 17 cell differentiation is mediated by Tripartite motif containing 28.

Epigenetic regulation is important for T-cell fate decision. Although STAT3 is known to initiate Th17 differentiation program, the downstream mechanism is unclear. Here we show that Tripartite motif containing 28 (Trim28) expression in Th17 cells is required for Th17-mediated cytokine production and experimental autoimmune diseases. Genome-wide occupancy analysis reveals that TRIM28-bound regions overlap with almost all Th17-specific super-enhancers (SE), and that those SEs are impaired by the deficiency of STAT3 or TRIM28, but not of RORγt. Importantly, IL-6-STAT3 signaling facilitates TRIM28 binding to the Il17-Il17f locus, and this process is required for epigenetic activation and high-order chromosomal interaction. TRIM28 also forms a complex with STAT3 and RORγt, and promotes the recruitment of RORγt to its target cytokine genes. Our study thus suggests TRIM28 to be important for the epigenetic activation during Th17 cell differentiation, and prompts the potential use of epigenetic interventions for Th17-related autoimmune diseases.

Downregulation of TRIM28 inhibits growth and increases apoptosis of nude mice with non­small cell lung cancer xenografts.

TRIM28 is a well­known transcriptional co­repressor of Kruppel­associated box zinc finger proteins. The authors previously demonstrated that TRIM28 small interfering (si)RNA decreases cell proliferation and inhibits cell cycle progression in non­small cell lung cancer (NSCLC) cell lines. The present study further demonstrated that the stable silencing of TRIM28 expression by a specific siRNA lentivirus vector significantly inhibited the growth and exerted obvious anti­tumor effects in nude mice. The results of the terminal deoxynucleotidyl transferase­mediated deoxyuridine triphosphate nick­end labeling assay indicated that TRIM28 knockdown increased apoptosis. Furthermore, TRIM28 knockdown decreased the expression of B cell lymphoma (Bcl)­2 and increased the expression of Bcl­2 associated X, apoptosis regulator and p53 at the gene and protein levels. Auto­antibodies to TRIM28 were present in 12.32% of the sera of the patients with NSCLC. The results suggest that TRIM28 knockdown may be effective against NSCLC, and TRIM28 antibodies have the potential to act as novel diagnostic and therapeutic tools.