Basophil differentiation, heterogeneity, and functional implications.

Basophils, rare granulocytes, have long been acknowledged for their roles in type 2 immune responses. However, the mechanisms by which basophils adapt their functions to diverse mammalian microenvironments remain unclear. Recent advancements in specific research tools and single-cell-based technologies have greatly enhanced our understanding of basophils. Several studies have shown that basophils play a role in maintaining homeostasis but can also contribute to pathology in various tissues and organs, including skin, lung, and others. Here, we provide an overview of recent basophil research, including cell development, characteristics, and functions. Based on an increasing understanding of basophil biology, we suggest that the precise targeting of basophil features might be beneficial in alleviating certain pathologies such as asthma, atopic dermatitis (AD), and others.

Identification and mechanism of G protein-biased ligands for chemokine receptor CCR1.

Biased signaling of G protein-coupled receptors describes an ability of different ligands that preferentially activate an alternative downstream signaling pathway. In this work, we identified and characterized different N-terminal truncations of endogenous chemokine CCL15 as balanced or biased agonists targeting CCR1, and presented three cryogenic-electron microscopy structures of the CCR1-Gi complex in the ligand-free form or bound to different CCL15 truncations with a resolution of 2.6-2.9 Å, illustrating the structural basis of natural biased signaling that initiates an inflammation response. Complemented with pharmacological and computational studies, these structures revealed it was the conformational change of Tyr291 (Y2917.43) in CCR1 that triggered its polar network rearrangement in the orthosteric binding pocket and allosterically regulated the activation of ß-arrestin signaling. Our structure of CCL15-bound CCR1 also exhibited a critical site for ligand binding distinct from many other chemokine-receptor complexes, providing new insights into the mode of chemokine recognition.

Molecular insights into ligand recognition and activation of chemokine receptors CCR2 and CCR3.

Chemokine receptors are a family of G-protein-coupled receptors with key roles in leukocyte migration and inflammatory responses. Here, we present cryo-electron microscopy structures of two human CC chemokine receptor-G-protein complexes: CCR2 bound to its endogenous ligand CCL2, and CCR3 in the apo state. The structure of the CCL2-CCR2-G-protein complex reveals that CCL2 inserts deeply into the extracellular half of the transmembrane domain, and forms substantial interactions with the receptor through the most N-terminal glutamine. Extensive hydrophobic and polar interactions are present between both two chemokine receptors and the Gα-protein, contributing to the constitutive activity of these receptors. Notably, complemented with functional experiments, the interactions around intracellular loop 2 of the receptors are found to be conserved and play a more critical role in G-protein activation than those around intracellular loop 3. Together, our findings provide structural insights into chemokine recognition and receptor activation, shedding lights on drug design targeting chemokine receptors.

Slp-coated liposomes for drug delivery and biomedical applications: potential and challenges.

Slp forms a crystalline array of proteins on the outermost envelope of bacteria and archaea with a molecular weight of 40-200 kDa. Slp can self-assemble on the surface of liposomes in a proper environment via electrostatic interactions, which could be employed to functionalize liposomes by forming Slp-coated liposomes for various applications. Among the molecular characteristics, the stability, adhesion, and immobilization of biomacromolecules are regarded as the most meaningful. Compared to plain liposomes, Slp-coated liposomes show excellent physicochemical and biological stabilities. Recently, Slp-coated liposomes were shown to specifically adhere to the gastrointestinal tract, which was attributed to the "ligand-receptor interaction" effect. Furthermore, Slp as a "bridge" can immobilize functional biomacromol-ecules on the surface of liposomes via protein fusion technology or intermolecular forces, endowing liposomes with beneficial functions. In view of these favorable features, Slp-coated liposomes are highly likely to be an ideal platform for drug delivery and biomedical uses. This review aims to provide a general framework for the structure and characteristics of Slp and the interactions between Slp and liposomes, to highlight the unique properties and drug delivery as well as the biomedical applications of the Slp-coated liposomes, and to discuss the ongoing challenges and perspectives.

Palmitoylation of NOD1 and NOD2 is required for bacterial sensing.

The nucleotide oligomerization domain (NOD)-like receptors 1 and 2 (NOD1/2) are intracellular pattern-recognition proteins that activate immune signaling pathways in response to peptidoglycans associated with microorganisms. Recruitment to bacteria-containing endosomes and other intracellular membranes is required for NOD1/2 signaling, and NOD1/2 mutations that disrupt membrane localization are associated with inflammatory bowel disease and other inflammatory conditions. However, little is known about this recruitment process. We found that NOD1/2 S-palmitoylation is required for membrane recruitment and immune signaling. ZDHHC5 was identified as the palmitoyltransferase responsible for this critical posttranslational modification, and several disease-associated mutations in NOD2 were found to be associated with defective S-palmitoylation. Thus, ZDHHC5-mediated S-palmitoylation of NOD1/2 is critical for their ability to respond to peptidoglycans and to mount an effective immune response.