National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
The Key Laboratory of Preventive Veterinary Medicine in Hubei Province, Cooperative Innovation Center for Sustainable Pig Production, Wuhan 430070, China.
Proc Natl Acad Sci U S A. 2024 Oct 29;121(44):e2409684121. doi: 10.1073/pnas.2409684121. Epub 2024 Oct 22.
To withstand complex microbial challenges, the mammalian gut largely depends on the secretion of diverse antimicrobial proteins. Type III interferons (IFNλs) are ordinarily considered inducible antiviral cytokines involved in intestinal immunity. Unlike other IFNλs, we found that newly identified IFNλ4 is an intestinal antibacterial protein. Large amounts of natural IFNλ4 are present in the secretory layer of the intestinal tracts of healthy piglets, which suggests that IFNλ4 is in direct physiological contact with microbial pathogens. We also identified two biochemical functions of mammalian IFNλ4, the induction of bacterial agglutination and direct microbial killing, which are not functions of the other IFNλs. Further mechanistic investigations revealed that after binding to the carbohydrate fraction of lipopolysaccharide, mammalian IFNλ4 self-assembles into bacteria-surrounding nanoparticles that agglutinate bacteria, and that its unique cationic amphiphilic molecular structure facilitates the destruction of bacterial membranes. Our data reveal features of IFNλ4 distinct from those of previously reported IFNλs and suggest that noncanonical IFNλ4 is deeply involved in intestinal immunity, beyond simply cytokine signaling.
为了抵御复杂的微生物挑战，哺乳动物肠道在很大程度上依赖于多种抗菌蛋白的分泌。III 型干扰素（IFNλs）通常被认为是参与肠道免疫的诱导型抗病毒细胞因子。与其他 IFNλs 不同，我们发现新鉴定的 IFNλ4 是一种肠道抗菌蛋白。大量天然 IFNλ4 存在于健康仔猪肠道的分泌层中，这表明 IFNλ4 与微生物病原体直接进行生理接触。我们还鉴定出了哺乳动物 IFNλ4 的两种生化功能，即细菌凝集的诱导和直接的微生物杀伤，而这些功能并非其他 IFNλs 所具有的。进一步的机制研究表明，与脂多糖的碳水化合物部分结合后，哺乳动物 IFNλ4 会自我组装成包围细菌的纳米颗粒，使细菌发生凝集，而其独特的阳离子两亲分子结构则有助于破坏细菌膜。我们的数据揭示了 IFNλ4 不同于先前报道的 IFNλs 的特征，并表明非典型 IFNλ4 深入参与了肠道免疫，而不仅仅是细胞因子信号转导。
