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The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species.

ABSTRACT: Cellular membrane proteins are a critical part of the host defense mechanisms against infection and intracellular survival of Listeria monocytogenes The complex spatiotemporal regulation of bacterial infection by various membrane proteins has been challenging to study. Here, using mass spectrometry analyses, we depicted the dynamic expression landscape of membrane proteins upon L. monocytogenes infection in dendritic cells. We showed that Dynein light chain 1 (Dynll1) formed a persistent complex with the mitochondrial cytochrome oxidase Cox4i1, which is disturbed by pathogen insult. We discovered that the dissociation of the Dynll1-Cox4i1 complex is required for the release of mitochondrial reactive oxygen species and serves as a regulator of intracellular proliferation of Listeria monocytogenes Our study shows that Dynll1 is an inhibitor of mitochondrial reactive oxygen species and can serve as a potential molecular drug target for antibacterial treatment.

SUBMITTER: Yuan J

PROVIDER: S-EPMC7093135 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species.

Yuan Jiangbei J Zheng Zihan Z Wang Liting L Ran Haiying H Tang Xiangyu X Xie Xiaodong X Li Fei F Liu Fang F Wang Xiaoyang X Zhang Jiale J Zhang Junying J Huang Yi Y Xia Xuefeng X Wan Ying Y

Infection and immunity 20200323 4

Cellular membrane proteins are a critical part of the host defense mechanisms against infection and intracellular survival of <i>Listeria monocytogenes</i> The complex spatiotemporal regulation of bacterial infection by various membrane proteins has been challenging to study. Here, using mass spectrometry analyses, we depicted the dynamic expression landscape of membrane proteins upon <i>L. monocytogenes</i> infection in dendritic cells. We showed that Dynein light chain 1 (Dynll1) formed a pers ...[more]

PMID: 32041786

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Project description:KRIT1 is a gene responsible for Cerebral Cavernous Malformations (CCM), a major cerebrovascular disease characterized by abnormally enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhage. Comprehensive analysis of the KRIT1 gene in CCM patients has suggested that KRIT1 functions need to be severely impaired for pathogenesis. However, the molecular and cellular functions of KRIT1 as well as CCM pathogenesis mechanisms are still research challenges. We found that KRIT1 plays an important role in molecular mechanisms involved in the maintenance of the intracellular Reactive Oxygen Species (ROS) homeostasis to prevent oxidative cellular damage. In particular, we demonstrate that KRIT1 loss/down-regulation is associated with a significant increase in intracellular ROS levels. Conversely, ROS levels in KRIT1(-/-) cells are significantly and dose-dependently reduced after restoration of KRIT1 expression. Moreover, we show that the modulation of intracellular ROS levels by KRIT1 loss/restoration is strictly correlated with the modulation of the expression of the antioxidant protein SOD2 as well as of the transcriptional factor FoxO1, a master regulator of cell responses to oxidative stress and a modulator of SOD2 levels. Furthermore, we show that the KRIT1-dependent maintenance of low ROS levels facilitates the downregulation of cyclin D1 expression required for cell transition from proliferative growth to quiescence. Finally, we demonstrate that the enhanced ROS levels in KRIT1(-/-) cells are associated with an increased cell susceptibility to oxidative DNA damage and a marked induction of the DNA damage sensor and repair gene Gadd45alpha, as well as with a decline of mitochondrial energy metabolism. Taken together, our results point to a new model where KRIT1 limits the accumulation of intracellular oxidants and prevents oxidative stress-mediated cellular dysfunction and DNA damage by enhancing the cell capacity to scavenge intracellular ROS through an antioxidant pathway involving FoxO1 and SOD2, thus providing novel and useful insights into the understanding of KRIT1 molecular and cellular functions.

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Dataset Information

The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species.

Publications

The Dynll1-Cox4i1 Complex Regulates Intracellular Pathogen Clearance via Release of Mitochondrial Reactive Oxygen Species.

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