The transforming growth factor beta ligand TIG-2 modulates the function of neuromuscular junction and muscle energy metabolism in Caenorhabditis elegans.

Deciphering the physiological function of TGF-ß (the transforming growth factor beta) family ligands is import for understanding the role of TGF-ß in animals' development and aging. Here, we investigate the function of TIG-2, one of the ligands in Caenorhabditis elegans TGF-ß family, in animals' behavioral modulation. Our results show that a loss-of-function mutation in tig-2 gene result in slower locomotion speed in the early adulthood and an increased density of cholinergic synapses, but a decreased neurotransmitter release at neuromuscular junctions (NMJs). Further tissue-specific rescue results reveal that neuronal and intestinal TIG-2 are essential for the formation of cholinergic synapses at NMJs. Interestingly, tig-2(ok3416) mutant is characterized with reduced muscle mitochondria content and adenosine triphosphate (ATP) production, although the function of muscle acetylcholine receptors and the morphology muscle fibers in the mutant are comparable to that in wild-type animals. Our result suggests that TIG-2 from different neuron and intestine regulates worm locomotion by modulating synaptogenesis and neurotransmission at NMJs, as well as energy metabolism in postsynaptic muscle cells.

Sexually Dimorphic Neurotransmitter Release at the Neuromuscular Junction in Adult Caenorhabditis elegans.

Sexually dimorphic differentiation of sex-shared behaviors is observed across the animal world, but the underlying neurobiological mechanisms are not fully understood. Here we report sexual dimorphism in neurotransmitter release at the neuromuscular junctions (NMJs) of adult Caenorhabditis elegans. Studying worm locomotion confirms sex differences in spontaneous locomotion of adult animals, and quantitative fluorescence analysis shows that excitatory cholinergic synapses, but not inhibitory GABAergic synapses exhibit the adult-specific difference in synaptic vesicles between males and hermaphrodites. Electrophysiological recording from the NMJ of C. elegans not only reveals an enhanced neurotransmitter release but also demonstrates increased sensitivity of synaptic exocytosis to extracellular calcium concentration in adult males. Furthermore, the cholinergic synapses in adult males are characterized with weaker synaptic depression but faster vesicle replenishment than that in hermaphrodites. Interestingly, T-type calcium channels/CCA-1 play a male-specific role in acetylcholine release at the NMJs in adult animals. Taken together, our results demonstrate sexually dimorphic differentiation of synaptic mechanisms at the C. elegans NMJs, and thus provide a new mechanistic insight into how biological sex shapes animal behaviors through sex-shared neurons and circuits.

USP38 Couples Histone Ubiquitination and Methylation via KDM5B to Resolve Inflammation.

Chromatin modifications, such as histone acetylation, ubiquitination, and methylation, play fundamental roles in maintaining chromatin architecture and regulating gene transcription. Although their crosstalk in chromatin remodeling has been gradually uncovered, the functional relationship between histone ubiquitination and methylation in regulating immunity and inflammation remains unclear. Here, it is reported that USP38 is a novel histone deubiquitinase that works together with the histone H3K4 modifier KDM5B to orchestrate inflammatory responses. USP38 specifically removes the monoubiquitin on H2B at lysine 120, which functions as a prerequisite for the subsequent recruitment of demethylase KDM5B to the promoters of proinflammatory cytokines Il6 and Il23a during LPS stimulation. KDM5B in turn inhibits the binding of NF-κB transcription factors to the Il6 and Il23a promoters by reducing H3K4 trimethylation. Furthermore, USP38 can bind to KDM5B and prevent it from proteasomal degradation, which further enhances the function of KDM5B in the regulation of inflammation-related genes. Loss of Usp38 in mice markedly enhances susceptibility to endotoxin shock and acute colitis, and these mice display a more severe inflammatory phenotype compared to wild-type mice. The studies identify USP38-KDM5B as a distinct chromatin modification complex that restrains inflammatory responses through manipulating the crosstalk of histone ubiquitination and methylation.

Caenorhabditis elegans body wall muscles sense mechanical signals with an amiloride-sensitive cation channel.

C. elegans uses specialized mechanoreceptor neurons to sense various mechanical cues. However, whether other tissues and organs in C. elegans are able to perceive mechanical forces is not clear. In this study, with a whole-cell patch-clamp recording, we show that body wall muscles (BWMs) in C. elegans convert mechanical energy into ionic currents in a cell-autonomous manner. Mechano-gated ion channels in BWMs are blocked in amiloride or cation-free solutions. A further characterization of physiological properties of mechano-gate ion channels in BMWs and a genetic screening show that mechanosensation in BMWs is not dependent on UNC-105 and well-defined mechano-gated ion channels MEC-4 and TRP-4 in C. elegans. Taken together, our results demonstrate that BWMs in C. elegans function as mechanoreceptors to sense mechanical stimuli with an amiloride-sensitive, non-selective cation channel.

TRIM14 Promotes Noncanonical NF-κB Activation by Modulating p100/p52 Stability via Selective Autophagy.

The noncanonical NF-κB signaling pathway plays a critical role in a variety of biological functions including chronic inflammation and tumorigenesis. Activation of noncanonical NF-κB signaling largely relies on the abundance as well as the processing of the NF-κB family member p100/p52. Here, TRIM14 is identified as a novel positive regulator of the noncanonical NF-κB signaling pathway. TRIM14 promotes noncanonical NF-κB activation by targeting p100/p52 in vitro and in vivo. Furthermore, a mechanistic study shows that TRIM14 recruits deubiquitinase USP14 to cleave the K63-linked ubiquitin chains of p100/p52 at multiple sites, thereby preventing p100/p52 from cargo receptor p62-mediated autophagic degradation. TRIM14 deficiency in mice significantly impairs noncanonical NF-κB-mediated inflammatory responses as well as acute colitis and colitis-associated colon cancer development. Taken together, these findings establish the TRIM14-USP14 axis as a crucial checkpoint that controls noncanonical NF-κB signaling and highlight the crosstalk between autophagy and innate immunity.

NLRP11 attenuates Toll-like receptor signalling by targeting TRAF6 for degradation via the ubiquitin ligase RNF19A.

The adaptor protein TRAF6 has a central function in Toll-like receptor (TLR) signalling, yet the molecular mechanisms controlling its activity and stability are unclear. Here we show that NLRP11, a primate specific gene, inhibits TLR signalling by targeting TRAF6 for degradation. NLRP11 recruits the ubiquitin ligase RNF19A to catalyze K48-linked ubiquitination of TRAF6 at multiple sites, thereby leading to the degradation of TRAF6. Furthermore, deficiency in either NLRP11 or RNF19A abrogates K48-linked ubiquitination and degradation of TRAF6, which promotes activation of NF-κB and MAPK signalling and increases the production of proinflammatory cytokines. Therefore, our findings identify NLRP11 as a conserved negative regulator of TLR signalling in primate cells and reveal a mechanism by which the NLRP11-RNF19A axis targets TRAF6 for degradation.

NLRP11 disrupts MAVS signalosome to inhibit type I interferon signaling and virus-induced apoptosis.

MAVS signalosome plays an important role in RIG-I-like receptor (RLR)-induced antiviral signaling. Upon the recognition of viral RNAs, RLRs activate MAVS, which further recruits TRAF6 and other signaling proteins to initiate type I interferon (IFN) activation. MAVS signalosome also regulates virus-induced apoptosis to limit viral replication. However, the mechanisms that control the activity of MAVS signalosome are still poorly defined. Here, we report NLRP11, a Nod-like receptor, is induced by type I IFN and translocates to mitochondria to interact with MAVS upon viral infection. Using MAVS as a platform, NLRP11 degrades TRAF6 to attenuate the production of type I IFNs as well as virus-induced apoptosis. Our findings reveal the regulatory role of NLRP11 in antiviral immunity by disrupting MAVS signalosome.