A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing.
A secreted microRNA disrupts autophagy in distinct tissues of Caenorhabditis elegans upon ageing.
复制标题
DOI：
10.1038/s41467-019-13698-x
复制
发表时间：
2019-01-01
影响因子：
16.6
通讯作者：
Shen, Y. D.
中科院分区：
文献类型：
--
作者：
Zhou, Yi-fei;Wang, Xue-qing;Shen, Y. D.
气道微生物组在哮喘病理生理学中具有重要作用。然而，对哮喘儿童的气道微生物组、哮喘控制丧失和严重急性发作之间的关系知之甚少。在这里，我们报告了微生物群的动态模式和组成与哮喘急性发作有关。我们在一项临床试验中，在一年内的两个时间点纵向收集了鼻吹气样本（n = 319）：哮喘得到控制时的随机化，以及哮喘早期失去控制时（黄色区域（YZ））。我们报告说，微生物群由RD的棒状杆菌+ Dolosigranulum簇主导的参与者经历最低的YZ率（p = 0.005），并且有更长的时间发展至少2次YZ发作（p = 0.03）。气道微生物群已从随机化变为YZ。从随机化时的棒状杆菌+ Dolosigranulum簇转换为YZ的莫拉氏菌-簇造成严重哮喘急性发作的最高风险（p = 0.04）。在YZ的棒状杆菌的相对丰度与严重的恶化呈负相关（p = 0.002）。提出了在蛋白质质量控制中的关键角色的大自噬在不同的组织中被系统性地损害，并导致整个身体的蛋白质稳态和衰老的协调破坏。虽然自噬和衰老的组织特异性变化已被广泛探索，但对组织间自噬随衰老的调节机制知之甚少。在这里，我们表明，分泌的microRNA，mir-83/miR-29，控制在秀丽隐杆线虫组织中与年龄相关的宏观自噬减少。随着年龄的增长，mir-83在肠道中被hsf-1/HSF 1上调，可能通过细胞外囊泡跨组织转运，并通过抑制CUP-5/MCOLN（一种重要的自噬调节剂）来破坏大自噬，其自主地在肠道中以及非自主地在体壁肌肉中。突变mir-83从而增强不同组织中的大自噬，促进蛋白质稳态和长寿。因此，这些发现确定了一种基于microRNA的机制，以协调各种组织中随着年龄的增长而减少的宏观自噬。
The airway microbiome has an important role in asthma pathophysiology. However, little is known on the relationships between the airway microbiome of asthmatic children, loss of asthma control, and severe exacerbations. Here we report that the microbiota's dynamic patterns and compositions are related to asthma exacerbations. We collected nasal blow samples (n = 319) longitudinally during a clinical trial at 2 time-points within one year: randomization when asthma is under control, and at time of early loss of asthma control (yellow zone (YZ)). We report that participants whose microbiota was dominated by the commensal Corynebacterium + Dolosigranulum cluster at RD experience the lowest rates of YZs (p = 0.005) and have longer time to develop at least 2 episodes of YZ (p = 0.03). The airway microbiota have changed from randomization to YZ. A switch from the Corynebacterium + Dolosigranulum cluster at randomization to the Moraxella- cluster at YZ poses the highest risk of severe asthma exacerbation (p = 0.04). Corynebacterium's relative abundance at YZ is inversely associated with severe exacerbation (p = 0.002).Macroautophagy, a key player in protein quality control, is proposed to be systematically impaired in distinct tissues and causes coordinated disruption of protein homeostasis and ageing throughout the body. Although tissue-specific changes in autophagy and ageing have been extensively explored, the mechanism underlying the inter-tissue regulation of autophagy with ageing is poorly understood. Here, we show that a secreted microRNA, mir-83/miR-29, controls the age-related decrease in macroautophagy across tissues in Caenorhabditis elegans. Upregulated in the intestine by hsf-1/HSF1 with age, mir-83 is transported across tissues potentially via extracellular vesicles and disrupts macroautophagy by suppressing CUP-5/MCOLN, a vital autophagy regulator, autonomously in the intestine as well as non-autonomously in body wall muscle. Mutating mir-83 thereby enhances macroautophagy in different tissues, promoting protein homeostasis and longevity. These findings thus identify a microRNA-based mechanism to coordinate the decreasing macroautophagy in various tissues with age.