TBK1-stabilized ZNF268a recruits SETD4 to methylate TBK1 for efficient interferon signaling.

Sufficient activation of interferon signaling is critical for the host to fight against invading viruses, in which post-translational modifications have been demonstrated to play a pivotal role. Here, we demonstrate that the human KRAB-zinc finger protein ZNF268a is essential for virus-induced interferon signaling. We find that cytoplasmic ZNF268a is constantly degraded by lysosome and thus remains low expressed in resting cell cytoplasm. Upon viral infection, TBK1 interacts with cytosolic ZNF268a to catalyze the phosphorylation of Serine 178 of ZNF268a, which prevents the degradation of ZNF268a, resulting in the stabilization and accumulation of ZNF268a in the cytoplasm. Furthermore, we provide evidence that stabilized ZNF268a recruits the lysine methyltransferase SETD4 to TBK1 to induce the mono-methylation of TBK1 on lysine 607, which is critical for the assembly of the TBK1 signaling complex. Notably, ZNF268 S178 is conserved among higher primates but absent in rodents. Meanwhile, rodent TBK1 607th aa happens to be replaced by arginine, possibly indicating a species-specific role of ZNF268a in regulating TBK1 during evolution. These findings reveal novel functions of ZNF268a and SETD4 in regulating antiviral interferon signaling.

RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation.

A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-ß induction. The overexpression of RNF138 inhibited the virus-induced activation of IRF3 and the transcription of the IFNB1 gene, whereas the knockout of RNF138 promoted the virus-induced activation of IRF3 and transcription of the IFNB1 gene. We further found that RNF138 promotes the ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for the PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses.

Engineering and Characterization of an Artificial Drug-Carrying Vesicles Nanoplatform for Enhanced Specifically Targeted Therapy of Glioblastoma.

Glioblastoma multiforme (GBM) treatment is hindered by complex pathologies and the need to cross the blood-brain barrier (BBB) during drug delivery. Although exosomes have great potential for GBM treatment, these alone cannot fully meet the therapeutic requirements, owing to their limitations in targeting and delivery. Herein, engineered artificial vesicles (EAVs), ANG-TRP-PK1@EAVs, which are constructed using a liposome extruder from HEK293T cells expressing ANG-TRP-PK1 peptides, is developed. ANG-TRP-PK1 is a fusion peptide of Angiopep-2 fused to the N-terminus of TRP-PK1, to present Angiopep-2 on the EAVs. ANG-TRP-PK1@EAVs have similar characteristics to the secreted exosomes, but a much higher yield. ANG-TRP-PK1@EAVs have efficient BBB-penetration and GBM-targeting abilities in a mock BBB model in in vitro and orthotopic GBM mouse models in vivo. Doxorubicin loading EAVs (ANG-TRP-PK1@DOX) do not alter the characteristics of the EAVs, which can cross the BBB, reach the GBM, and kill tumor cells in orthotopic GBM mouse models. These engineered drug-loaded artificial vesicles show better therapeutic effects on GBM than temozolomide in mice, with very few side effects. In conclusion, EAVs can be inserted into different targeting ligands and packed into different drugs, and they may serve as unique and efficient nanoplatforms for drug delivery and tumor promise therapy.

Blockade of JAK2 retards cartilage degeneration and IL-6-induced pain amplification in osteoarthritis.

Osteoarthritis (OA) is a complex chronic inflammatory disease characterized by articular degeneration and pain. Recent studies have identified interleukin 6 (IL-6) as a potential mediator leading to OA, but the therapeutic effects of inhibiting IL-6 signaling in intreating OA need to be further clarified. Here, we identified the intracellular signal transduction induced by recombinant IL-6 and focused on the impact of tyrphostin AG490 (a JAK2 inhibitor) on cartilage degeneration and OA pain. We found that IL-6 increased the inflammatory cytokines production and hypertrophic markers expression of primary mouse chondrocytes by activating JAK2/STAT3. Meanwhile, tyrphostin AG490 significantly attenuated articular degeneration and osteophyte formation in experimental mice with anterior cruciate ligament transection (ACLT) surgery. In vivo electrophysiological experiments showed that articular stimulation of IL-6 induced spinal hyperexcitability, which was prevented by coinjection of tyrphostin AG490. Specifically, compared with DMSO-treated ACLT mice, tyrphostin AG490 improved ambulate activity of mice and abolished the enhancement of serum bradykinin induced by IL-6. Together, we suggest that tyrphostin AG490 protected against progression of OA and improved OA prognosis by reducing cartilage degeneration and arthritis pain. Our findings provide further evidence for targeting IL-6 signaling in the treatment of OA.

[Research on the dynamics of ion debris from Sn plasma by use of dual laser pulses].

Extreme ultraviolet lithography is one of the most promising technologies on the next generation of high-capacity integrated circuit manufacturing. However, techniques for ion debris mitigation have to be considered in the application of extreme ultraviolet source for lithography. In our paper the dynamics of ion debris from Sn plasma by using dual ns laser pulses were investigated. The results show that debris from plasma greatly depends on the energy of pre-pulse and the delay time between the two laser pulses. The energy of Sn ions debris was efficiently mitigated from 2. 47 to 0. 40 keV in the case of dual laser pulses, up to 6. 1 times lower than that by using single laser pulse. We also found that Sn ions debris can be mitigated at all angles by using the dual laser pulses method.