+1 credit
| Version | Summary | Created by | Modification | Content Size | Created at | Operation |
|---|---|---|---|---|---|---|
| 1 | Steve Catarino | + 556 word(s) | 556 | 2020-04-30 06:03:10 | | | |
| 2 | Camila Xu | -2 word(s) | 554 | 2020-10-30 09:39:35 | | |
Video Upload Options
Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cx), which provide direct communication between adjacent cells, allowing for the passage of small molecules and ions. GJ intercellular communication can be modulated through gating of the channel pore and also through mechanisms that regulate the amount of connexin-containing channels at the plasma membrane
1. Introduction
Connexins (Cx) are a family of proteins that directly connect the cytoplasm of adjacent cells through the formation of gap junction (GJ) channels. In humans, twenty members form the connexin family, while at least seventeen members have been reported in rats. Based on sequence homology, connexin genes can be grouped into four classes, α, β, γ and δ [1]. Each connexin consists of four transmembrane regions, two extracellular loops and one intracellular loop, with both the amino and carboxyl terminals facing the cytosol. After synthesis, connexin proteins oligomerize into hexameric structures termed hemichannels and are transported to the plasma membrane, where they may dock to hemichannels from adjacent cells to form a functional GJ channel. The carboxyl terminal is where most differences between connexins are found, and a large part of the protein interactions and post-translational modifications of connexins are thought to occur in this region [2]. Although traditionally associated with establishing direct communication between adjacent cells, the localization of connexins at the plasma membrane as undocked connexin hemichannels as well as its presence in mitochondria, nucleus and extracellular vesicles, suggest that connexins play other non-canonical biological roles [3]. Given all of the above, fine-tuned regulatory mechanisms are required to modulate connexin levels, function and localization.
2. Discussion
Although GJ intercellular communication can be modulated through the gating of the channel pore, mechanisms that regulate the number of connexin-containing channels at the plasma membrane have also been implicated in the regulation of intercellular communication. Given the short half-life of Cx43, the most widely expressed and studied Cx family member, mechanisms of protein degradation play an important role in the regulation of Cx43 levels and intercellular communication. Ubiquitination of Cx43, modulated by E3 ligases, including neural precursor cell expressed developmentally down-regulated protein 4 (Nedd4), and deubiquitinating enzymes, such as associated molecule with the SH3 domain of STAM (AMSH), dictates the final fate of the protein [4][5][6][7]. At the plasma membrane, Cx43 is modified by Lysine 63-linked polyubiquitin chains, which are recognized by the endocytic adaptor epidermal growth factor receptor substrate 15 (Eps15) to trigger the internalization of the protein [7]. Furthermore, Cx43 sorting from early endosomes to the lysosome is also reliant on ubiquitination to mediate the interaction with the endosomal sorting complex required for transport (ESCRT) components hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and tumour susceptibility gene 101 (Tsg101) [8][9]. The role of Cx43 ubiquitination in signalling lysosomal GJ degradation is important not only in the endocytic pathway but also in the autophagy process. Indeed, GJ degradation by macroautophagy is also dependent, at least partially, on prior ubiquitination of Cx43 [10][11], a process that requires not only the ubiquitin-binding domain containing autophagy receptor p62, but also, and surprisingly, the endocytic adaptor Eps15 [11]. However, preventing the ubiquitination of Cx43 did not fully abrogate its autophagic degradation, suggesting that alternative mechanisms for targeting Cx43 to autophagosomes exist. Notably, a conserved LC3 interacting region (LIR) motif has been described in connexins, and has been shown to mediate the interaction of MAPLC3B and GABARAP with Cx37, Cx43, Cx46 and Cx50 [12].
References
- Eric C Beyer; Gregory M. Lipkind; John W. Kyle; Viviana M. Berthoud; Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure.. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2011, 1818, 1823-30, 10.1016/j.bbamem.2011.10.011.
- J C Hervé; N. Bourmeyster; Denis Sarrouilhe; Heather S. Duffy; Gap junctional complexes: From partners to functions. Progress in Biophysics and Molecular Biology 2007, 94, 29-65, 10.1016/j.pbiomolbio.2007.03.010.
- Tânia Martins-Marques; Teresa M Ribeiro-Rodrigues; Daniela Almeida; Trond Aasen; Brenda R. Kwak; Henrique Girão; Biological Functions of Connexin43 Beyond Intercellular Communication.. Trends in Cell Biology 2019, 29, 835-847, 10.1016/j.tcb.2019.07.001.
- Teresa M Ribeiro-Rodrigues; Steve Catarino; Maria João Pinho; P.C. Pereira; Henrique Girão; Connexin 43 ubiquitination determines the fate of gap junctions: restrict to survive. Biochemical Society Transactions 2015, 43, 471-475, 10.1042/bst20150036.
- Henrique Girão; Steve Catarino; P.C. Pereira; Eps15 interacts with ubiquitinated Cx43 and mediates its internalization. Experimental Cell Research 2009, 315, 3587-3597, 10.1016/j.yexcr.2009.10.003.
- Steve Catarino; Jose Ramalho; Carla Marques; P.C. Pereira; Henrique Girão; Ubiquitin-mediated internalization of connexin43 is independent of the canonical endocytic tyrosine-sorting signal. Biochemical Journal 2011, 437, 255-267, 10.1042/bj20102059.
- Teresa M Ribeiro-Rodrigues; Steve Catarino; Carla Marques; João Vasco Ferreira; Tânia Martins-Marques; P.C. Pereira; Henrique Girão; AMSH‐mediated deubiquitination of Cx43 regulates internalization and degradation of gap junctions. The FASEB Journal 2014, 28, 4629-4641, 10.1096/fj.13-248963.
- Tanja Auth; Sharazad Schlüter; Stephanie Urschel; Petra Kussmann; Stephan Sonntag; Thorsten Höher; Maria M. Kreuzberg; Radek Dobrowolski; Klaus Willecke; The TSG101 protein binds to connexins and is involved in connexin degradation. Experimental Cell Research 2009, 315, 1053-1062, 10.1016/j.yexcr.2008.12.025.
- Edward Leithe; A. Kjenseth; S. Sirnes; H. Stenmark; A. Brech; E. Rivedal; Ubiquitylation of the gap junction protein connexin-43 signals its trafficking from early endosomes to lysosomes in a process mediated by Hrs and Tsg101. Journal of Cell Science 2009, 122, 3883-3893, 10.1242/jcs.053801.
- John T. Fong; Rachael M. Kells; Anna M. Gumpert; Jutta Y. Marzillier; Michael W. Davidson; Matthias M. Falk; Internalized gap junctions are degraded by autophagy.. Autophagy 2012, 8, 794-811, 10.4161/auto.19390.
- Eloy Bejarano; Henrique Girão; Andrea Yuste; Bindi Patel; Carla Marques; David C. Spray; P.C. Pereira; Ana Maria Cuervo; Autophagy modulates dynamics of connexins at the plasma membrane in a ubiquitin-dependent manner. Molecular Biology of the Cell 2012, 23, 2156-2169, 10.1091/mbc.E11-10-0844.
- Steve Catarino; Teresa M Ribeiro-Rodrigues; Rita Sá Ferreira; José Ramalho; Christine Abert; Sascha Martens; Henrique Girão; A Conserved LIR Motif in Connexins Mediates Ubiquitin-Independent Binding to LC3/GABARAP Proteins. Cells 2020, 9, 902, 10.3390/cells9040902.
