Heparan sulfate is a clearance receptor for aberrant extracellular proteins

Itakura, Eisuke; Chiba, Momoka; Murata, Takeshi; Matsuura, Akira

doi:10.1083/jcb.201911126

Cited by 43 publications

(51 citation statements)

References 65 publications

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“…Human clusterin is considered an extracellular chaperone that can bind to misfolded proteins and then undergo degradation. A recent study revealed the mechanisms by which clusterin clears misfolded proteins: clusterin binds to heparan sulfate through electrostatic interaction, is transported into the cell through the heparan sulfate receptor on the cell surface and then is degraded in lysosome [ 36 ]. This pathway could promote the degradation of amyloid beta peptide, which explains why clusterin is associated with Alzheimer's disease [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

A puzzle piece of protein N-glycosylation in chicken egg: N-glycoproteome of chicken egg vitelline membrane

Xiao

Wang

Cheng

et al. 2020

International Journal of Biological Macromolecules

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The chicken egg vitelline membrane (CEVM) is an important structure for the transmembrane transport of egg yolk components, protection of the blastodisc, and separation of egg white and egg yolk. In this study, the N-glycoproteome of the CEVM was mapped and analyzed in depth. Total protein of the CEVM was digested, and the glycopeptides were enriched by a hydrophilic interaction liquid chromatography microcolumn and identified by nano liquid chromatography/tandem mass spectrometry. A total of 435 N-glycosylation sites on 208 N-glycoproteins were identified in CEVM. Gene Ontology enrichment analysis showed that CEVM N-glycoproteins are mainly involved in the regulation of proteinases/inhibitors and transmembrane transport of lipids. Mucin-5B is the primary N-glycoprotein in the CEVM. Comparison of the main N-glycoproteins between the CEVM and other egg parts revealed the tissue specificity of N-glycosylation of egg proteins. The results provide insights into protein N-glycosylation in the chicken egg, CEVM functions and underlying mechanisms.

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Section: Resultsmentioning

confidence: 99%

A puzzle piece of protein N-glycosylation in chicken egg: N-glycoproteome of chicken egg vitelline membrane

Xiao

Wang

Cheng

et al. 2020

International Journal of Biological Macromolecules

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“…Clusterin mediates the clearance from the plasma (via the liver and kidney) and CSF (via transcytosis across the blood–brain barrier (BBB) of a variety of client proteins ( Figure 2 , panel 1). Clusterin also promotes endocytosis and degradation via non-professional phagocytic cells, through binding cell surface HSPGs ( Itakura et al, 2020 ) ( Figure 2 , panel 2) and via microglial cells by binding the surface receptor TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) ( Yeh et al, 2016 ) ( Figure 2 , panel 3). Similar membrane receptors in brain cells promote extracellular clearance of client-chaperone complexes.…”

Section: Discussionmentioning

confidence: 99%

“…In vivo , clusterin promotes transcytosis of Abeta across the blood–brain barrier through [lipoprotein-related protein 2 (LRP2)-mediated endocytosis] ( Zlokovic, 1996 ; Wojtas et al, 2017 ). More broadly, clusterin has been shown to promote internalization and degradation of cellular debris and misfolded proteins in non-professional phagocytic cells through LRP2 ( Bartl et al, 2001 ) and through HSPGs ( Itakura et al, 2020 ). Itakura et al (2020) demonstrated that clusterin binds HSPGs through an electrostatic interaction to promote co-degradation of clusterin and client proteins.…”

Section: Clusterinmentioning

confidence: 99%

“…More broadly, clusterin has been shown to promote internalization and degradation of cellular debris and misfolded proteins in non-professional phagocytic cells through LRP2 ( Bartl et al, 2001 ) and through HSPGs ( Itakura et al, 2020 ). Itakura et al (2020) demonstrated that clusterin binds HSPGs through an electrostatic interaction to promote co-degradation of clusterin and client proteins. HSPGs are broadly expressed and have been previously linked to the endocytosis of a variety of ligands (reviewed in Sarrazin et al, 2011 ), including Abeta ( Kanekiyo et al, 2011 ), among others.…”

Section: Clusterinmentioning

confidence: 99%

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Secreted Chaperones in Neurodegeneration

Chaplot

Jarvela

Lindberg

2020

Front. Aging Neurosci.

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Protein homeostasis, or proteostasis, is a combination of cellular processes that govern protein quality control, namely, protein translation, folding, processing, and degradation. Disruptions in these processes can lead to protein misfolding and aggregation. Proteostatic disruption can lead to cellular changes such as endoplasmic reticulum or oxidative stress; organelle dysfunction; and, if continued, to cell death. A majority of neurodegenerative diseases involve the pathologic aggregation of proteins that subverts normal neuronal function. While prior reviews of neuronal proteostasis in neurodegenerative processes have focused on cytoplasmic chaperones, there is increasing evidence that chaperones secreted both by neurons and other brain cells in the extracellular – including transsynaptic – space play important roles in neuronal proteostasis. In this review, we will introduce various secreted chaperones involved in neurodegeneration. We begin with clusterin and discuss its identification in various protein aggregates, and the use of increased cerebrospinal fluid (CSF) clusterin as a potential biomarker and as a potential therapeutic. Our next secreted chaperone is progranulin; polymorphisms in this gene represent a known genetic risk factor for frontotemporal lobar degeneration, and progranulin overexpression has been found to be effective in reducing Alzheimer’s- and Parkinson’s-like neurodegenerative phenotypes in mouse models. We move on to BRICHOS domain-containing proteins, a family of proteins containing highly potent anti-amyloidogenic activity; we summarize studies describing the biochemical mechanisms by which recombinant BRICHOS protein might serve as a therapeutic agent. The next section of the review is devoted to the secreted chaperones 7B2 and proSAAS, small neuronal proteins which are packaged together with neuropeptides and released during synaptic activity. Since proteins can be secreted by both classical secretory and non-classical mechanisms, we also review the small heat shock proteins (sHsps) that can be secreted from the cytoplasm to the extracellular environment and provide evidence for their involvement in extracellular proteostasis and neuroprotection. Our goal in this review focusing on extracellular chaperones in neurodegenerative disease is to summarize the most recent literature relating to neurodegeneration for each secreted chaperone; to identify any common mechanisms; and to point out areas of similarity as well as differences between the secreted chaperones identified to date.

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“…While the mechanisms of intracellular protein quality control are well known, the quality control machinery for extracellular proteins, which are subjected to more stringent environmental conditions, is largely hidden in a veil of mystery. In the current issue, Itakura et al identified a mechanism by which aberrant extracellular proteins are transported into cells in a receptor-mediated manner to degrade them in the lysosome (1).…”

mentioning

confidence: 99%