Dynamic RBM47 ISGylation confers broad immunoprotection against lung injury and tumorigenesis via TSC22D3 downregulation.

ISGylation is a well-established antiviral mechanism, but its specific function in immune and tissue homeostasis regulation remains elusive. Here, we reveal that the RNA-binding protein RBM47 undergoes phosphorylation-dependent ISGylation at lysine 329 to regulate immune activation and maintain lung homeostasis. K329R knockin (KI) mice with defective RBM47-ISGylation display heightened susceptibility to LPS-induced acute lung injury and lung tumorigenesis, accompanied with multifaceted immunosuppression characterized by elevated pro-inflammatory factors, reduced IFNs/related chemokines, increased myeloid-derived suppressor cells, and impaired tertiary lymphoid structures. Mechanistically, RBM47-ISGylation regulation of the expression of TSC22D3 mRNA, a glucocorticoid-inducible transcription factor, partially accounts for the effects of RBM47-ISGylation deficiency due to its broad immunosuppressive activity. We further demonstrate the direct inhibitory effect of RBM47-ISGylation on TSC22D3 expression in human cells using a nanobody-targeted E3 ligase to induce site-specific ISGylation. Furthermore, epinephrine-induced S309 phosphorylation primes RBM47-ISGylation, with epinephrine treatment exacerbating dysregulated cytokine expression and ALI induction in K329R KI mice. Our findings provide mechanistic insights into the dynamic regulation of RBM47-ISGylation in supporting immune activation and maintaining lung homeostasis.

Effects of endovascular recanalization on symptomatic non-acute occlusion of intracranial arteries.

To investigate the effect and safety of recanalization surgery for non-acute occlusion of large intracranial arteries and factors affecting clincial outcomes. Patients with non-acute occlusion of internal carotid artery (ICA), middle cerebral artery (MCA), and vertebrobasilar artery (VBA) treated with recanalization were retrospectively enrolled. The clinical and angiographic data were analyzed. 177 patients were enrolled, including 67 patients with intracranial ICA occlusion, 52 with MCA occlusion, and 58 with VBA occlusion. Successful recanalization was achieved in 152 (85.9%) patients. Complications occurred in 15 patients (8.5%). Followed up for 3-7 months, the 90 day mRS was significantly improved compared with that before the procedure. Among 152 patients with successful recanalization, eight patients experienced reocclusion (5.3%), and 11 patients experienced restenosis (7.2%). Successful recanalization was significantly (P < 0.05) associated with occlusion duration, calcification or angulation of the occluded segment. Complications were significantly (P < 0.05) associated with location of occlusion, hyperlipidemia, and patients' height. Restentosis or reocclusion at follow-up was significantly (P < 0.05) associated with complications and mRS at 90 days. The significant (P < 0.05) independent risk factors were angulation and calcification for successful recanalization, hyperlipidemia for complications, and mRS at 90 days for restenosis or reocclusion at follow-up. Recanalization surgery may be a safe and effective approach for patients with non-acute symptomatic occlusion of large intracranial arteries, and factors significantly independently associated with successful recanalization, periprocedural complications and restenosis or reocclusion after surgery have been identified for future reference to improve clinical outcomes.

Role of autophagy and mTOR signaling in neural differentiation of bone marrow mesenchymal stem cells.

Autophagy is involved in cell differentiation. We present evidence that autophagy is activated during ß-mercaptoethanol (ß-ME)-induced neuronal differentiation of bone marrow mesenchymal stem cells (MSCs), in which mammalian target of rapamycin (mTOR) signaling is important. mTOR activity declined after being transported from the nucleus to the cytoplasm. Using 3-methyladenine (3-MA) and rapamycin to regulate the activity of mTOR, it was found that the efficiency of neuronal differentiation was affected.

MicroRNA-9 regulates neural apoptosis in methylmalonic acidemia via targeting BCL2L11.

Methylmalonic acidemia (MMA) is an autosomal-recessive inborn metabolic disorder that results from a deficiency in methylmalonyl-coenzyme A mutase or its cofactor, adenosylcobalamin. Currently, neurological manifestations in MMA are thought to be associated with neural apoptosis. BCL2L11, which is a proapoptotic Bcl-2 family member, is resident in the outer mitochondrial membrane, where this protein acts as a central regulator of the intrinsic apoptotic cascade and mediates excitotoxic apoptosis. MicroRNAs (miRNAs) are a class of non-coding RNAs that function as endogenous triggers of the RNA interference pathway. Currently, little is known regarding the role of miRNA in MMA. In our previous study, we preliminarily found that the expression of miR-9 was significantly down-regulated in MMA patient plasma and sensitively changed after VitB12 treatment, which may act as a potential "competitor" of gas chromatography-mass spectrometry for the diagnosis of MMA. In the present study, we first confirmed that miR-9 inhibited BCL2L11 expression by directly targeting its 3'-untranslated region, and the up-regulation of miR-9 reduced neural apoptosis induced by methylmalonate via targeting BCL2L11. Taken together, our results suggested that miR-9 might act as a monitor of changes in MMA and might provide new insights into a therapeutic entry point for treating MMA.