About: Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling

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About: Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling
Creator	Proud, Christopher Fedele, Anthony
source	PMC
abstract	Autophagy is dependent upon lysosomes, which fuse with the autophagosome to complete the autophagic process and whose acidic interior permits the activity of their intraluminal degradative enzymes. Chloroquine (CQ) and bafilomycin A1 (BafA) each cause alkalinisation of the lumen and thus impair lysosomal function, although by distinct mechanisms. CQ diffuses into lysosomes and undergoes protonation, while BafA inhibits the ability of the vacuolar type H(+)-ATPase (v-ATPase) to transfer protons into the lysosome. In the present study, we examine the impact of CQ and BafA on the activity of mammalian target of rapamycin complex 1 (mTORC1), inhibition of which is an early step in promoting autophagy. We find each compound inhibits mTORC1 signalling, without affecting levels of protein components of the mTORC1 signalling pathway. Furthermore, these effects are not related to these agents’ capacity to inhibit autophagy or the reduction in amino acid supply from lysosomal proteolysis. Instead, our data indicate that the reduction in mTORC1 signalling appears to be due to the accumulation of lysosomal storage material. However, there are differences in responses to these agents, for instance, in their abilities to up-regulate direct targets of transcription factor EB (TFEB), a substrate of mTORC1 that drives transcription of many lysosomal and autophagy-related genes. Nonetheless, our data imply that widely used agents that alkalinise intralysosomal pH are mimetics of acute lysosomal storage disorders (LSDs) and emphasise the importance of considering the result of CQ and BafA on mTORC1 signalling when interpreting the effects of these agents on cellular physiology.
has issue date	2020-04-28(xsd:dateTime)
bibo:doi	10.1042/bsr20200905
bibo:pmid	32285908
has license	cc-by
sha1sum (hex)	3b45489e57a93648e455f0ef47892355cc930a5b
schema:url	https://doi.org/10.1042/bsr20200905
resource representing a document's title	Chloroquine and bafilomycin A mimic lysosomal storage disorders and impair mTORC1 signalling
has PubMed Central identifier	PMC7189491
has PubMed identifier	32285908
schema:publication	Biosci Rep
resource representing a document's body	covid:3b45489e57a93648e455f0ef47892355cc930a5b#body_text
is schema:about of	named entity 'signalling' named entity 'intraluminal' named entity 'mechanisms' named entity 'mimic' named entity 'autophagic' »more»

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