Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations.

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dc.contributor.authorXu, H.
dc.contributor.authorIsenmann, S.
dc.contributor.authorLópez-Hernández, T.
dc.contributor.authorEstévez, R.
dc.contributor.authorLukacs, G.L.
dc.contributor.authorApaja, P.M.
dc.date.issued2021
dc.description.abstractThe significance of crosstalks among constituents of plasma membrane protein clusters/complexes in cellular proteostasis and protein quality control (PQC) remains incompletely understood. Examining the glial (enriched) cell adhesion molecule (CAM), we demonstrate its chaperone-like role in the biosynthetic processing of the megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1)-heteromeric regulatory membrane protein complex, as well as the function of the GlialCAM/MLC1 signalling complex. We show that in the absence of GlialCAM, newly synthesized MLC1 molecules remain unfolded and are susceptible to polyubiquitination-dependent proteasomal degradation at the endoplasmic reticulum. At the plasma membrane, GlialCAM regulates the diffusional partitioning and endocytic dynamics of cluster members, including the ClC-2 chloride channel and MLC1. Impaired folding and/or expression of GlialCAM or MLC1 in the presence of diseases causing mutations, as well as plasma membrane tethering compromise the functional expression of the cluster, leading to compromised endo-lysosomal organellar identity. In addition, the enlarged endo-lysosomal compartments display accelerated acidification, ubiquitinated cargo-sorting and impaired endosomal recycling. Jointly, these observations indicate an essential and previously unrecognized role for CAM, where GliaCAM functions as a PQC factor for the MLC1 signalling complex biogenesis and possess a permissive role in the membrane dynamic and cargo sorting functions with implications in modulations of receptor signalling.
dc.description.statementofresponsibilityHaijin Xu, Sandra Isenmann, Tania López-Hernández, Raúl Estévez, Gergely L. Lukacs, Pirjo M. Apaja
dc.identifier.citationScientific Reports, 2021; 11(1):18435-1-18435-17
dc.identifier.doi10.1038/s41598-021-97777-4
dc.identifier.issn2045-2322
dc.identifier.issn2045-2322
dc.identifier.orcidApaja, P.M. [0000-0002-1622-2332]
dc.identifier.urihttps://hdl.handle.net/2440/146196
dc.language.isoen
dc.publisherSpringer Science and Business Media LLC
dc.rights© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
dc.source.urihttps://doi.org/10.1038/s41598-021-97777-4
dc.subjectCell biology; Endocytosis; Endoplasmic reticulum; Glial biology; Mechanisms of disease
dc.subject.meshAstrocytes
dc.subject.meshCells, Cultured
dc.subject.meshHela Cells
dc.subject.meshEndosomes
dc.subject.meshLysosomes
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshRats
dc.subject.meshChloride Channels
dc.subject.meshCell Adhesion Molecules
dc.subject.meshMembrane Proteins
dc.subject.meshProteostasis
dc.titleControl of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations.
dc.typeJournal article
pubs.publication-statusPublished

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