OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.

Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.

Listerin promotes cGAS protein degradation through the ESCRT pathway to negatively regulate cGAS-mediated immune response.

The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.

25 mJ, 5 KHz, 3 ns, Nd:YAG discrete path slab amplifier using a hybrid resonator.

We report what we believe to be potential improved performance for a Nd:YAG discrete path slab amplifier configuration based on a hybrid resonator system. The amplifier is driven by a Q-switched 0.3 mJ nanosecond oscillator that generates an initial laser pulse at a repetition rate of 5 KHz and has beam quality of M2<1.3. The input pulse makes 12 passes through the slab amplifier to yield 25 mJ output pulse energy at the absorbed pump power of 878 W. A corresponding optical-to-optical efficiency of 14.3% was obtained, and the beam quality factors M2 in the unstable and stable direction were 1.7 and 1.5, respectively. No detectable signs of amplified spontaneous emission were observed.

8.4mJ, 10kHz, 3.6ns, Nd:YVO4 slab amplifier.

A diode-pumped nanosecond eight-pass amplifier with Nd:YVO4 crystal was developed. Combined with the advantages of direct pumped and Innoslab structure, a high energy pulse was obtained by using the wedged multi-folded configuration with two plane mirrors. The 0.4mJ Q-switched seed at the pulse repetition frequency of 10kHz was amplified to 8.4mJ with the pump power of 330W, and the corresponding optical-to-optical efficiency was 29.8%. The M2 factors in the horizontal direction and vertical direction were 1.48 and 1.39, respectively. And no remarkable of ASE was observed.