Cytosolic Immune Surveillance During Bacterial Infections

炎性小体感知一系列病原体相关分子模式（PAMP）， 在感染和创伤过程中产生的损伤相关分子模式（DAMP）， 是抵抗感染的第一道防线在规范形式中，炎性小体由 识别PAMPs的传感器蛋白、衔接分子ASC和效应蛋白酶， 半胱天冬酶-1。在非规范形式中，与caspase-1相关的炎性caspase，即 caspase-11和caspase-4，直接从革兰氏阴性菌中检测到胞质脂多糖（LPS）。 阴性菌及其外膜囊泡。炎症体信号传导在 IL-1β、IL-18、gasdermin D（一种成孔蛋白）的翻译后活化和细胞凋亡， 细胞死亡的溶解和炎症形式，以及DAMP的同时释放。尽管 炎性小体反应在感染、癌症和自身免疫中的深远意义， 调节炎症小体信号传导起始和终止的调控模块仍然存在， 大部分是未知的。本建议旨在全面解决这一关键的知识差距， 三个具体的目标，重点是半乳糖凝集素，一个家庭的β-半乳糖苷结合蛋白。由于 它们与各种糖蛋白的N-或O-聚糖末端结合并调节其功能的能力 由于半乳糖凝集素在细胞膜定位和信号转导中的作用， 生理和病理过程。该提案的目的1和2将研究半乳糖凝集素的 在鼠和人细胞以及体内的非典型炎性体信号传导中的作用。目标3将 探索半乳糖凝集素如何在体外和体内控制典型炎性体信号传导。总的来说， 该项目的发现将揭示炎性小体信号传导中的新参与者， 对人类传染病和败血症的影响。

Inflammasomes sense an array of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) generated during infection and trauma and represent the first line of defense against infections. In the canonical form, inflammasomes consist of a sensor protein that recognizes PAMPs, an adaptor molecule ASC, and an effector protease, caspase-1. In the noncanonical form, inflammatory caspases related to caspase-1, namely caspase-11 and caspase-4, directly sense cytosolic lipopolysaccharide (LPS) from Gram- negative bacteria and their outer membrane vesicle. Inflammasome signaling culminates in the post-translational activation of IL-1β, IL-18, gasdermin D (a pore-forming protein), and pyroptosis, a lytic and inflammatory form of cell death, and the simultaneous release of DAMPs. Despite the profound implications of inflammasome responses in infections, cancer, and autoimmunity, the regulatory modules that fine-tune the initiation and termination of inflammasome signaling remain mostly unknown. This proposal seeks to comprehensively address this critical knowledge gap in three specific aims by focusing on galectins, a family of β-galactoside-binding proteins. Owing to their capacity to bind to N- or O-glycan termini of various glycoproteins and regulate their membrane localization and signal transduction, galectins have diverse functions in various physiological and pathological processes. Aims 1 and 2 of the proposal will investigate galectins' role in noncanonical inflammasome signaling in murine and human cells and in vivo. Aim 3 will explore how galectins control canonical inflammasome signaling in vitro and in vivo. In summary, the findings from this project would reveal new players in inflammasome signaling with significant implications for human infectious diseases and sepsis.