Neutrophils contribute to pathogen clearance by producing neutrophil extracellular traps (NETs), which are genomic DNA-based net-like structures that capture bacteria and fungi. Although NETs also express antiviral factors, such as myeloperoxidase and α-defensin, the involvement of NETs in antiviral responses remains unclear. We show that NETs capture human immunodeficiency virus (HIV)-1 and promote HIV-1 elimination through myeloperoxidase and α-defensin. Neutrophils detect HIV-1 by Toll-like receptors (TLRs) TLR7 and TLR8, which recognize viral nucleic acids. Engagement of TLR7 and TLR8 induces the generation of reactive oxygen species that trigger NET formation, leading to NET-dependent HIV-1 elimination. However, HIV-1 counteracts this response by inducing C-type lectin CD209-dependent production of interleukin (IL)-10 by dendritic cells to inhibit NET formation. IL-10 suppresses the reactive oxygen species-dependent generation of NETs induced upon TLR7 and TLR8 engagement, resulting in disrupted NET-dependent HIV-1 elimination. Therefore, NET formation is an antiviral response that is counteracted by HIV-1.

The C-terminal region of Clostridium perfringens enterotoxin (C-CPE) can bind to specific claudins, resulting in the disintegration of tight junctions (TJs) and an increase in the paracellular permeability across epithelial cell sheets. Here we present the structure of mammalian claudin-19 in complex with C-CPE at 3.7 Å resolution. The structure shows that C-CPE forms extensive hydrophobic and hydrophilic interactions with the two extracellular segments of claudin-19. The claudin-19/C-CPE complex shows no density of a short extracellular helix that is critical for claudins to assemble into TJ strands. The helix displacement may thus underlie C-CPE-mediated disassembly of TJs.

The nuclear factor-B (NF-B) transcription factors play important roles in cancer development by preventing apoptosis and facilitating the tumor cell growth. However, the precise mechanisms by which NF-B is constitutively activated in specific cancer cells remain largely unknown. In our current study, we now report that NF-B-inducing kinase (NIK) is overexpressed at the pretranslational IntroductionThe nuclear factor-B (NF-B) transcription factors are known to regulate the expression of a wide range of genes involved in development, immune responses, apoptosis, and carcinogenesis as dimers of the REL family members, RelA, RelB, c-Rel, p50, and p52. 1 The p50 and p52 proteins are generated by proteasomemediated processing of their precursors, p105 and p100, respectively. In resting cells, Rel proteins are sequestered in the cytoplasm through their interactions with the ankyrin repeats of the inhibitory proteins IB␣, -␤, and -⑀, as well as the precursor proteins p105 and p100. On stimulation, signals converge at the multiprotein IB kinase (IKK) complex, which is composed of 2 catalytic subunits, IKK1/␣ and IKK2/␤, and the scaffolding proteins, NF-B essential modulator (NEMO, also known as IKK␥) and ELKS. 2 Phosphorylation by the IKK complex of specific serine residues on the IB or precursor proteins results in their poly-ubiquitination and proteasome-dependent degradation or processing. 2 Released NF-B then translocates to the nucleus and regulates expression of target genes.NF-B signaling pathways are largely classified as either canonical or noncanonical based on the stimuli and targets of the IKK complex. 2 Canonical activation is induced by stimuli, such as tumor necrosis factor-␣ (TNF␣) and interleukin-1␤, and involves NEMO-and IKK2/␤-dependent phosphorylation and the subsequent degradation of IB proteins. Noncanonical NF-B pathways are activated after the stimulation of a range of TNF receptor family members, such as B-cell activating factor belonging to the TNF family (BAFF) receptor, lymphotoxin-␤ receptor, Fn14 and CD40, and direct NF-B-inducing kinase (NIK)-and IKK1/␣-dependent phosphorylation and subsequent processing of p100, leading to activation of NF-B complexes containing RelB. 2,3 Of note in this context, the noncanonical pathways operate in a delayed fashion and are sensitive to protein synthesis inhibition. 4,5 Compared with the mechanisms underlying the transduction of ligand-induced signaling to NF-B activation, much less is known about how NF-B is constitutively activated in a variety of cancer cells. 6 Constitutively high NF-B activity has typically been demonstrated in human hematopoietic cancer cells, including adult T-cell leukemia (ATL), Hodgkin lymphoma, and multiple myeloma cells. 7,8 We have previously reported the aberrant expression of p52 in ATL and Hodgkin Reed-Sternberg (H-RS) cells that do not express viral regulatory proteins, such as Tax of the human T-cell leukemia virus or latent membrane protein 1 of the Epstein-Barr virus. 9,10 In addition, IKK activation in ATL and H-RS c...

Tight junction is a cell adhesion apparatus functioning as barrier and/or channel in the paracellular spaces of epithelia. Claudin is the major component of tight junction and polymerizes to form tight junction strands with various morphologies that may correlate with their functions. Here we present the crystal structure of mammalian claudin-3 at 3.6 Å resolution. The third transmembrane helix of claudin-3 is clearly bent compared with that of other subtypes. Structural analysis of additional two mutants with a single mutation representing other subtypes in the third helix indicates that this helix takes a bent or straight structure depending on the residue. The presence or absence of the helix bending changes the positions of residues related to claudin-claudin interactions and affects the morphology and adhesiveness of the tight junction strands. These results evoke a model for tight junction strand formation with different morphologies – straight or curvy strands – observed in native epithelia.