In biology, as almost anywhere else, a rope tied to a piece of paper is a little bit more than a cat teaser. It's a kite, it's an ornament, it's a shopping bag. In their recently published manuscript 1, Abascal and Zardoya convincingly demonstrated that a small army of scientists happily digging into the recently discovered family of vertebrate innexin orthologs absentmindedly overlooked a whole new baby – LRRC8s, a “sister” family with transmembrane domain folds closely resembling these of pannexins. What do we know about mammalian pannexins? At the same time, both aplenty and absolutely nothing. A cursory look into the current crop of publications – in year 2012, alone – clearly demonstrates that novel study avenues are sprouting like the tentacles of an octopus. Pannexin 1 forms ion and metabolite permeable hexameric channels abundantly expressed in the brain where they regulate the proliferation of neural stem and progenitor cells 2. In the colon, these channels are activated by inflammation that opens them up, thus, causing the death of the neurons and the loss of gut motility 3. Finally, PANX1 channels were shown to regulate the 3D assembly of cancer cells, thus, being pivotal to the progression of tumors 4. With a track record like that, could we really expect that the newly discovered LRRC8 paralogues would behave as non-descript team players somewhere in the middle of the cellular milieu? Let us have a closer look at the novel addition to the pannexin family. In LRRC8s, four transmembrane domains typical for hemichannel forming pannexins are augmented by leucine-repeat rich (LRR) domains found in many other, non-pannexin related, but extremely peculiar protein families, for example, in pathogen sensing Toll-like receptors of animals and in nucleotide-binding LRR proteins defining the plant pathogen resistance. Interestingly, in both of these LRR-containing protein families, the LRR domains point outside of the cells, while in the model presented by Abascal and Zardoya, these LRRs point inside. It is tempting to speculate that the binding of LRRs to some cytoplasmic molecules, proteins or otherwise, may regulate the opening of the pannexin-like channel structures of LRRC8s. The million dollars question is: what binds to these intracellular LRR tails? Abascal and Zardoya suggest that LRRC8s play a role in intercellular communications, a conclusion that is derived from the known roles of non-pannexin-like LRR proteins with intracellular locations. A quick look at the databases of summarized experimental data describing known protein-protein interactions of LRRC8s revealed an intriguing picture firmly placing LRRC8A as a component of the assembly of the pre-B cell receptor (pre-BCR), which acts as an important checkpoint at the pro-B/preB transitional stage, while both LRCC8B and LRCC8C have something to do in the nucleus. LRCC8B interacts with nesprin-1 (SYNE1) crucial for nuclear envelope integrity, while LRCC8C binds to sterol regulatory element binding protein-lc (SREBP-lc), three different transcription factors of CCAAT/enhancer binding protein (CEBP) family, CEBPA, CEBPB, and CEBPD, as well as FANCD2 known to be involved in DNA damage-induced S-phase arrest and crosslink repair. Additionally, LRCC8C is implicated in the regulation of basic metabolism, as evident by its binding to the circadian deadenylase nocturnin that influences traffic of dietary lipid in intestinal enterocytes and modulates early adipogenesis along with transcriptional factors already mentioned above. It seems that putative functions for LRRC8s are budding. To open up another avenue for speculations, I cannot avoid the temptation to throw in one more hypothesis: what if LRCC8s break away from the traditional model of the cellular pathway by sending signals from inside out? Clearly, these proteins are very well equipped to do just that – their intracellular LRRs are capable of protein-protein or small molecule interactions, while their pannexin-like domain should be able to open and close in response to the change in the conformation of attached LRRs, allowing ions and/or other second messengers to quickly come out. Doing this, LRRC8s may serve as permanently inserted molecular dipsticks that rapidly signal to adjacent cells about some dangerous change happening within an individual cell as it goes awry. Of course, this is just a speculation, not better nor worse than others being written, but oh so exciting!
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Jan 13, 2014
Silvia Penuela + 6
Open Access
