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

Abstract The 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...

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Autores principales:	Haijin Xu, Sandra Isenmann, Tania López-Hernández, Raúl Estévez, Gergely L. Lukacs, Pirjo M. Apaja
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/eca27c5cd8744f3faa3f91b5a2225771
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spelling	oai:doaj.org-article:eca27c5cd8744f3faa3f91b5a22257712021-12-02T17:25:43ZControl of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations10.1038/s41598-021-97777-42045-2322https://doaj.org/article/eca27c5cd8744f3faa3f91b5a22257712021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97777-4https://doaj.org/toc/2045-2322Abstract The 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.Haijin XuSandra IsenmannTania López-HernándezRaúl EstévezGergely L. LukacsPirjo M. ApajaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Haijin Xu Sandra Isenmann Tania López-Hernández Raúl Estévez Gergely L. Lukacs Pirjo M. Apaja Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
description	Abstract The 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.
format	article
author	Haijin Xu Sandra Isenmann Tania López-Hernández Raúl Estévez Gergely L. Lukacs Pirjo M. Apaja
author_facet	Haijin Xu Sandra Isenmann Tania López-Hernández Raúl Estévez Gergely L. Lukacs Pirjo M. Apaja
author_sort	Haijin Xu
title	Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
title_short	Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
title_full	Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
title_fullStr	Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
title_full_unstemmed	Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
title_sort	control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/eca27c5cd8744f3faa3f91b5a2225771
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Control of membrane protein homeostasis by a chaperone-like glial cell adhesion molecule at multiple subcellular locations

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