Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P53675 (CHC22)
 19 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intracellular trafficking of the glucose transporter GLUT4 from storage compartments to the plasma membrane is triggered in muscle and fat during the body's response to insulin. Clathrin is involved in intracellular trafficking, and in humans, the clathrin heavy-chain isoform CHC22 is highly expressed in skeletal muscle. We found a role for CHC22 in the formation of insulin-responsive GLUT4 compartments in human muscle and adipocytes. CHC22 also associated with expanded GLUT4 compartments in muscle from type 2 diabetic patients. Tissue-specific introduction of CHC22 in mice, which have only a pseudogene for this protein, caused aberrant localization of GLUT4 transport pathway components in their muscle, as well as features of diabetes. Thus, CHC22-dependent membrane trafficking constitutes a species-restricted pathway in human muscle and fat with potential implications for type 2 diabetes.
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PMID:A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism. 1947 73

Clathrin is considered the prototype vesicle coat protein whose self-assembly mediates sorting of membrane cargo and recruitment of lipid modifiers. Detailed knowledge of clathrin biochemistry, structure, and interacting proteins has accumulated since the first observation, almost 50 years ago, of its role in receptor-mediated endocytosis of yolk protein. This review summarizes that knowledge, and focuses on properties of the clathrin heavy and light chain subunits and interaction of the latter with Hip proteins, to address the diversity of clathrin function beyond conventional receptor-mediated endocytosis. The distinct functions of the two human clathrin isoforms (CHC17 and CHC22) are discussed, highlighting CHC22's specialized involvement in traffic of the GLUT4 glucose transporter and consequent role in human glucose metabolism. Analysis of clathrin light chain function and interaction with the actin-binding Hip proteins during bacterial infection defines a novel actin-organizing function for CHC17 clathrin. By considering these diverse clathrin functions, along with intracellular sorting roles and influences on mitosis, further relevance of clathrin function to human health and disease is established.
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PMID:Diversity of clathrin function: new tricks for an old protein. 2283 40

Mobilization of the GLUT4 glucose transporter from intracellular storage vesicles provides a mechanism for insulin-responsive glucose import into skeletal muscle. In humans, clathrin isoform CHC22 participates in formation of the GLUT4 storage compartment in skeletal muscle and fat. CHC22 function is limited to retrograde endosomal sorting and is restricted in its tissue expression and species distribution compared to the conserved CHC17 isoform that mediates endocytosis and several other membrane traffic pathways. Previously, we noted that CHC22 was expressed at elevated levels in regenerating rat muscle. Here we investigate whether the GLUT4 pathway in which CHC22 participates could play a role in muscle regeneration in humans and we test this possibility using CHC22-transgenic mice, which do not normally express CHC22. We observed that GLUT4 expression is elevated in parallel with that of CHC22 in regenerating skeletal muscle fibers from patients with inflammatory and other myopathies. Regenerating human myofibers displayed concurrent increases in expression of VAMP2, another regulator of GLUT4 transport. Regenerating fibers from wild-type mouse skeletal muscle injected with cardiotoxin also showed increased levels of GLUT4 and VAMP2. We previously demonstrated that transgenic mice expressing CHC22 in their muscle over-sequester GLUT4 and VAMP2 and have defective GLUT4 trafficking leading to diabetic symptoms. In this study, we find that muscle regeneration rates in CHC22 mice were delayed compared to wild-type mice, and myoblasts isolated from these mice did not proliferate in response to glucose. Additionally, CHC22-expressing mouse muscle displayed a fiber type switch from oxidative to glycolytic, similar to that observed in type 2 diabetic patients. These observations implicate the pathway for GLUT4 transport in regeneration of both human and mouse skeletal muscle, and demonstrate a role for this pathway in maintenance of muscle fiber type. Extrapolating these findings, CHC22 and GLUT4 can be considered markers of muscle regeneration in humans.
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PMID:The CHC22 clathrin-GLUT4 transport pathway contributes to skeletal muscle regeneration. 2420 66

CHC22 clathrin plays a key role in intracellular membrane traffic of the insulin-responsive glucose transporter GLUT4 in humans. We performed population genetic and phylogenetic analyses of the CHC22-encoding CLTCL1 gene, revealing independent gene loss in at least two vertebrate lineages, after arising from gene duplication. All vertebrates retained the paralogous CLTC gene encoding CHC17 clathrin, which mediates endocytosis. For vertebrates retaining CLTCL1, strong evidence for purifying selection supports CHC22 functionality. All human populations maintained two high frequency CLTCL1 allelic variants, encoding either methionine or valine at position 1316. Functional studies indicated that CHC22-V1316, which is more frequent in farming populations than in hunter-gatherers, has different cellular dynamics than M1316-CHC22 and is less effective at controlling GLUT4 membrane traffic, altering its insulin-regulated response. These analyses suggest that ancestral human dietary change influenced selection of allotypes that affect CHC22's role in metabolism and have potential to differentially influence the human insulin response.
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PMID:Genetic diversity of CHC22 clathrin impacts its function in glucose metabolism. 3115 24

Insulin stimulates glucose transport by triggering regulated delivery of intracellular vesicles containing the GLUT4 glucose transporter to the plasma membrane. This process is defective in diseases such as type 2 diabetes (T2DM). While studies in rodent cells have been invaluable in understanding GLUT4 traffic, evolutionary plasticity must be considered when extrapolating these findings to humans. Recent work has identified species-specific distinctions in GLUT4 traffic, notably the participation of a novel clathrin isoform, CHC22, in humans but not rodents. Here, we discuss GLUT4 sorting in different species and how studies of CHC22 have identified new routes for GLUT4 trafficking. We further consider how different sorting-protein complexes relate to these routes and discuss other implications of these pathways in cell biology and disease.
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PMID:Building GLUT4 Vesicles: CHC22 Clathrin's Human Touch. 3262 May 16