Structural basis for GTP-induced dimerization and antiviral function of guanylate-binding proteins.

Guanylate-binding proteins (GBPs) form a family of dynamin-related large GTPases which mediate important innate immune functions. They were proposed to form oligomers upon GTP binding/hydrolysis, but the molecular mechanisms remain elusive. Here, we present crystal structures of C-terminally truncated human GBP5 (hGBP51-486), comprising the large GTPase (LG) and middle (MD) domains, in both its nucleotide-free monomeric and nucleotide-bound dimeric states, together with nucleotide-free full-length human GBP2. Upon GTP-loading, hGBP51-486 forms a closed face-to-face dimer. The MD of hGBP5 undergoes a drastic movement relative to its LG domain and forms extensive interactions with the LG domain and MD of the pairing molecule. Disrupting the MD interface (for hGBP5) or mutating the hinge region (for hGBP2/5) impairs their ability to inhibit HIV-1. Our results point to a GTP-induced dimerization mode that is likely conserved among all GBP members and provide insights into the molecular determinants of their antiviral function.

Highly Stretchable and Stimulus-Free Self-Healing Hydrogels with Multiple Signal Detection Performance for Self-Powered Wearable Temperature Sensors.

A flexible wearable temperature sensor is a novel electronic sensor that can monitor real-time changes in human body temperature in a variety of application scenarios and is regarded as the "crown jewel" of information collection technology. Although flexible strain sensors based on hydrogels have excellent self-healing effects and mechanical durability, their widespread application is still limited by external power sources. Herein, a novel self-energizing hydrogel was developed by embellishing cellulose nanocrystals (CNC) with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). The resultant thermoelectrically conductive CNC was then employed as a booster for poly(vinyl alcohol) (PVA)/borax hydrogels. The obtained hydrogels exhibit remarkable self-healing performance (92.57%) and exceptional stretchability (989.60%). Additionally, the hydrogel was capable of accurately and reliably identifying human motion. Most importantly, it exhibits excellent thermoelectric performance, capable of generating stable and reproducible voltages. It shows a large Seebeck coefficient of 1.31 mV k-1 at ambient temperatures. When subjected to a temperature difference of 25 K, the output voltage reaches 31.72 mV. CNC-PEDOT:PSS/PVA conductive hydrogel is multifunctional with self-healing, self-powering, and temperature sensing, which has the potential to be used for the preparation of intelligent wearable temperature-sensing devices.

METTL16-mediated translation of CIDEA promotes non-alcoholic fatty liver disease progression via m6A-dependent manner.

Background: As the most prevalent chemical modifications on eukaryotic mRNAs, N6-methyladenosine (m6A) methylation was reported to participate in the regulation of various metabolic diseases. This study aimed to investigate the roles of m6A methylation and methyltransferase-like16 (METTL16) in non-alcoholic fatty liver disease (NAFLD). Methods: In this study, we used a model of diet-induced NAFLD, maintaining six male C57BL/6J mice on high-fat diet (HFD) to generate hepatic steatosis. The high-throughput sequencing and RNA sequencing were performed to identify the m6A methylation patterns and differentially expressed mRNAs in HFD mice livers. Furthermore, we detected the expression levels of m6A modify enzymes by qRT-PCR in liver tissues, and further investigated the potential role of METTL16 in NAFLD through constructing overexpression and a knockdown model of METTL16 in HepG2 cells. Results: In total, we confirmed 15,999 m6A recurrent peaks in HFD mice and 12,322 in the control. Genes with differentially methylated m6A peaks were significantly associated with the dysregulated glucolipid metabolism and aggravated hepatic inflammatory response. In addition, we identified five genes (CIDEA, THRSP, OSBPL3, GDF15 and LGALS1) that played important roles in NAFLD progression after analyzing the differentially expressed genes containing differentially methylated m6A peaks. Intriguingly, we found that the expression levels of METTL16 were substantially increased in the NAFLD model in vivo and in vitro, and further confirmed that METTL16 upregulated the expression level of lipogenic genes CIDEA in HepG2 cells. Conclusions: These results indicate the critical roles of m6A methylation and METTL16 in HFD-induced mice and cell NAFLD models, which broaden people's perspectives on potential m6A-related treatments and biomarkers for NAFLD.