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Introduction. Shigella flexneri is an intracellular bacterial pathogen that utilizes a type III secretion apparatus to inject effector proteins into host cells. Hypothesis/Gap Statement. The T3SS effector IpaH4.5 is important for the virulence of Shigella . Aim. This study aimed to elucidate the molecular mechanism and host target of the IpaH4.5 as well as its roles in S. flexneri infection. Methodology. The GAP assay was used to identify substrate Rab GTPases of IpaH4.5. A coimmunoprecipitation assay was applied to identify the interaction of Rab GTPases with IpaH4.5. A confocal microscopy analysis was used to assess the effects of IpaH4.5 on mannose 6-phosphate receptor (MPR) trafficking. To identify the effects of IpaH4.5 GAP activity on the activity of lysosomal cathepsin B, the Magic Red-RR assay was used. Finally, the intracellular persistence assay was used to identify IpaH4.5 GAP activity in S. flexneri intracellular growth. Results. We found that the effector IpaH4.5 disrupts MPR trafficking and lysosomal function, thereby counteracting host lysosomal degradation. IpaH4.5 harbours TBC-like dual-finger motifs and exhibits potent RabGAP activities towards Rab31. IpaH4.5 disrupts the transport of the cation-dependent mannose 6-phosphate receptor (CD-MPR) from the Golgi to the endosome by targeting Rab31, thereby attenuating lysosomal function. As a result, the intracellular persistence of S. flexneri requires IpaH4.5 TBC-like GAP activity to mediate bacterial escape from host lysosome-mediated elimination. Conclusion. We identified an unknown function of IpaH4.5 and its potential role in S. flexneri infection.

Activation of the NLRP3 inflammasome requires the expression of NLRP3, which is strictly regulated by its capacity to directly recognize microbial-derived substances. Even though the involvement of caspase-1 activation in macrophages via NLRP3 and NLRC4 has been discovered, the accurate mechanisms by which Shigella infection triggers NLRP3 activation remain inadequately understood. Here, we demonstrate that IpaH4.5, a Shigella T3SS effector, triggers inflammasome activation by regulating NLRP3 expression through the E3 ubiquitin ligase activity of IpaH4.5. First, we found that IpaH4.5 interacted with NLRP3. As a result, IpaH4.5 modulated NLRP3 protein stability and inflammasome activation. Bacteria lacking IpaH4.5 had dramatically reduced ability to induce pyroptosis. Our results identify a previously unrecognized target of IpaH4.5 in the regulation of inflammasome signaling and clarify the molecular basis for the cytosolic response to the T3SS effector.

The recently emerged pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly, leading to a global COVID-19 pandemic. Binding of the viral spike protein (SARS-2-S) to cell surface receptor angiotensin-converting enzyme 2 (ACE2) mediates host cell infection. In the present study, we demonstrate that in addition to ACE2, the S1 subunit of SARS-2-S binds to HDL and that SARS-CoV-2 hijacks the SR-B1-mediated HDL uptake pathway to facilitate its entry. SR-B1 facilitates SARS-CoV-2 entry into permissive cells by augmenting virus attachment. MAb (monoclonal antibody)-mediated blocking of SARS-2-S-HDL binding and SR-B1 antagonists strongly inhibit HDL-enhanced SARS-CoV-2 infection. Notably, SR-B1 is co-expressed with ACE2 in human pulmonary and extrapulmonary tissues. These findings revealed a novel mechanism for SARS-CoV-2 entry and could provide a new target to treat SARS-CoV-2 infection.

Transparent conducting electrodes based on silver nanowires (AgNWs) have arisen great interest due to their excellent photoelectric properties compared with the conventional sputtered indium tin oxide (ITO) electrodes. However, the practical applications of these electrodes are limited due to their coarse surface morphology, weak mechanical adhesion and high junction resistivity as well as poor thermal and chemical stability. In this work, we develop a new processing technique to resolve all above limitations by embedding random AgNWs networks in solution-processed conductive aluminum-doped zinc oxide nanoparticles (AZO-NPs) matrices via a spin-coating process at low temperature (150 °C). Our results show that coating the AZO-NPs on the surface of AgNWs networks effectively fill the holes between AgNWs and tightened the AgNWs junctions, resulting in ultralow surface roughness and excellent wire-substrate mechanical adhesion. Surrounding the AgNWs by conductive AZO-NPs could provide more electron transport channels between AgNWs so as to improve the wire-wire electrical conductivity. The resulting composite electrodes demonstrated an excellent performance with low sheet resistivity 91% at 550 nm, excellent thermal stability at temperature as high as 270 °C, good chemical corrosion resistance, and retained high electrical conductivity showing less 1% deviation in sheet resistivity after 300 continuous convex and concave bending cycle. Kesterite pure sulfide Cu2ZnSnS4 thin film solar cells using such composite electrodes as top contact show a best conversion efficiency of 7.45%, achieving a 11.5% increase compared with conventionally sputtered ITO-based CZTS thin film solar cells due to higher short circuit current density and fill factor.

Summary: Recent reports have shown the critical role of the mitochondrial antiviral signaling (MAVS) protein in virus-induced apoptosis, but the involvement of MAVS in tumorigenesis is still poorly understood. Herein, we report that MAVS is a key regulator of p53 activation and is critical for protecting against tumorigenesis. We find that MAVS promotes p53-dependent cell death in response to DNA damage. MAVS interacts with p53 and mediates p53 mitochondrial recruitment under genotoxic stress. Mechanistically, MAVS inhibits p53 ubiquitination by blocking the formation of the p53-murine double-minute 2 (MDM2) complex, leading to the stabilization of p53. Notably, compared with their wild-type littermates, MAVS knockout mice display decreased resistance to azoxymethane (AOM) or AOM/dextran sulfate sodium salt (DSS)-induced colon cancer. MAVS expression is significantly downregulated in human colon cancer tissues. These results unveil roles for MAVS in DNA damage response and tumor suppression. : Zhang et al. show that MAVS interacts with p53 and regulates p53-dependent apoptosis, indicating roles for MAVS in tumor suppression and the DNA damage response. Keywords: MAVS, p53, ubiquitination, tumor suppression