Dai Li-Li, Gao Jin-Xia, Zou Cheng-Gang, Ma Yi-Cheng, Zhang Ke-Qin
Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, Kunming, Yunnan, China.
PLoS Pathog. 2015 Jan 8;11(1):e1004606. doi: 10.1371/journal.ppat.1004606. eCollection 2015 Jan.
The unfolded protein response (UPR), which is activated by perturbations of the endoplasmic reticulum homeostasis, has been shown to play an important role in innate immunity and inflammation. However, little is known about the molecular mechanisms underlying activation of the UPR during immune responses. Using small RNA deep sequencing and reverse genetic analysis, we show that the microRNA mir-233 is required for activation of the UPR in Caenorhabditis elegans exposed to Pseudomonas aeruginosa PA14. P. aeruginosa infection up-regulates the expression of mir-233 in a p38 MAPK-dependent manner. Quantitative proteomic analysis identifies SCA-1, a C. elegans homologue of the sarco/endoplasmic reticulum Ca2+-ATPase, as a target of mir-233. During P. aeruginosa PA14 infection, mir-233 represses the protein levels of SCA-1, which in turn leads to activation of the UPR. Whereas mir-233 mutants are more sensitive to P. aeruginosa infection, knockdown of sca-1 leads to enhanced resistance to the killing by P. aeruginosa. Our study indicates that microRNA-dependent pathways may have an impact on innate immunity by activating the UPR.
未折叠蛋白反应（UPR）由内质网稳态的扰动激活，已被证明在先天免疫和炎症中起重要作用。然而，关于免疫反应期间UPR激活的分子机制知之甚少。通过小RNA深度测序和反向遗传分析，我们发现秀丽隐杆线虫暴露于铜绿假单胞菌PA14时，微小RNA mir-233是激活UPR所必需的。铜绿假单胞菌感染以p38丝裂原活化蛋白激酶依赖的方式上调mir-233的表达。定量蛋白质组学分析确定SCA-1（肌浆网/内质网Ca2+ -ATP酶的秀丽隐杆线虫同源物）为mir-233的靶标。在铜绿假单胞菌PA14感染期间，mir-233抑制SCA-1的蛋白质水平，进而导致UPR的激活。虽然mir-233突变体对铜绿假单胞菌感染更敏感，但敲低sca-1会增强对铜绿假单胞菌杀伤的抵抗力。我们的研究表明，微小RNA依赖的途径可能通过激活UPR对先天免疫产生影响。
