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Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression.

ABSTRACT: An important feature of long-term synaptic plasticity is the prolonged maintenance of plastic changes in synaptic transmission. The trafficking of AMPA-type glutamate receptors (AMPARs) is involved in the expression of many forms of synaptic plasticity, yet the subsequent events accomplishing the maintenance of plastic changes in synaptic AMPAR numbers are not fully understood. Here, we find that maintenance of cerebellar long-term depression results from a reduction in the number of AMPARs residing within endocytic recycling pathways. We then develop a genetically encoded, photosensitive inhibitor of late endosome sorting and use this to discover that initial maintenance of long-term depression relies on timely regulated late endosome sorting, which exhibits a threshold as well as switch-like behavior. Thus, our results indicate that recycling AMPAR numbers are reduced by a switching machinery of transient late endosome sorting, and that this process enables the transition from basal synaptic transmission to long-term depression maintenance.Long term depression (LTD) of the cerebellum is known to be mediated by postsynaptic trafficking of glutamate receptor AMPAR. Here, Kim and colleagues show that early- to late-endosomal sorting of AMPAR represents the switch from expression to maintenance phase of cerebellar LTD.

SUBMITTER: Kim T

PROVIDER: S-EPMC5581341 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression.

Kim Taegon T Yamamoto Yukio Y Tanaka-Yamamoto Keiko K

Nature communications 20170901 1

An important feature of long-term synaptic plasticity is the prolonged maintenance of plastic changes in synaptic transmission. The trafficking of AMPA-type glutamate receptors (AMPARs) is involved in the expression of many forms of synaptic plasticity, yet the subsequent events accomplishing the maintenance of plastic changes in synaptic AMPAR numbers are not fully understood. Here, we find that maintenance of cerebellar long-term depression results from a reduction in the number of AMPARs resi ...[more]

PMID: 28864821

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Project description:UnlabelledHuman cathepsin W (CtsW) is a cysteine protease, which was identified in a genome-wide RNA interference (RNAi) screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs.ImportanceIncreasing levels of resistance of influenza viruses to available antiviral drugs have been observed. Development of novel treatment options is therefore of high priority. In parallel to the classical approach of targeting viral enzymes, a novel strategy is pursued: cell-dependent factors of the virus are identified with the aim of developing small-molecule inhibitors against a cellular target that the virus relies on. For influenza A virus, several genome-wide RNA interference (RNAi) screens revealed hundreds of potential cellular targets. However, we have only limited knowledge on how these factors support virus replication, which would be required for drug development. We have characterized cathepsin W, one of the candidate factors, and found that cathepsin W is required for escape of influenza virus from the late endosome. Importantly, this required the proteolytic activity of cathepsin W. We therefore suggest that cathepsin W could be a target for future host cell-directed antiviral therapies.

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Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression.

Publications

Timely regulated sorting from early to late endosomes is required to maintain cerebellar long-term depression.

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