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
- Autophagy
- Cx43
- GABARAP
- Gap junction
- MAPLC3
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].
This entry is adapted from the peer-reviewed paper 10.3390/cells9040902
References
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