LRRC8A

LRRC8A
Identifiers
AliasesLRRC8A, AGM5, LRRC8, SWELL1, leucine-rich repeat containing 8 family member A, leucine rich repeat containing 8 family member A, leucine rich repeat containing 8 VRAC subunit A, HsLRRC8A
External IDsOMIM: 608360; MGI: 2652847; GeneCards: LRRC8A
Orthologs
DatabasesNCBI: entry; OMA: entry
SpeciesHumanMouse
Entrez

56262

241296

Ensembl

ENSG00000136802

ENSMUSG00000007476

UniProt

Q8IWT6

Q80WG5

RefSeq (mRNA)

NM_001127244
NM_001127245
NM_019594

NM_177725

RefSeq (protein)

NP_001120716
NP_001120717
NP_062540

NP_808393

Location (UCSC)Chr 9: 128.88 – 128.92 MbChr 2: 30.13 – 30.15 Mb
PubMed search
Wikidata
View/Edit HumanView/Edit Mouse

Leucine-rich repeat-containing protein 8A is a protein that in humans is encoded by the LRRC8A gene.

Structure

LRRC8A is a subunit of the heteromeric volume-regulated anion channel (VRAC), which also contains other members of the LRRC8 protein family: LRRC8B, LRRC8C, LRRC8D or LRRC8E. The transmembrane regions of LRRC8 proteins are similar to those of pannexins.

LRRC8A alone can assemble into homohexameric channels. Structures of mouse and human LRRC8A channels have been determined by cryo-electron microscopy.

Function

VRACs contribute to cell-volume regulation by transporting chloride ions and organic osmolytes, including taurine and glutamate, across the plasma membrane. LRRC8A is required for VRAC function, but is insufficient on its own to reproduce the full range of typical VRAC activity. The other LRRC8 subunits influence the channel's substrate specificity.

LRRC8A-containing VRACs also transport cyclic-GMP-AMP (cGAMP), allowing extracellular cGAMP to enter cells and activate the cGAS–STING cytosolic DNA sensing pathway. This activity has been identified in channels containing LRRC8A together with LRRC8C or LRRC8E. Mice lacking LRRC8E show reduced interferon responses and impaired immunity following HSV-1 infection. LRRC8 channels can transport cGAMP in either direction according to its electrochemical gradient, although their physiological contribution to cGAMP export remains unclear.

Clinical signficance

A congenital mutation in LRRC8A has been associated with agammaglobulinemia-5.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000136802 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000007476 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: LRRC8A leucine rich repeat containing 8 family, member A".
  6. ↑ Voss FK, Ullrich F, Münch J, Lazarow K, Lutter D, Mah N, et al. (May 2014). "Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC". Science. 344 (6184). New York, N.Y.: 634–638. Bibcode:2014Sci...344..634V. doi:10.1126/science.1252826. PMID 24790029. S2CID 24709412.
  7. ↑ Abascal F, Zardoya R (July 2012). "LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication". BioEssays. 34 (7): 551–560. doi:10.1002/bies.201100173. hdl:10261/124027. PMID 22532330. S2CID 24648128.
  8. ↑ Deneka D, Sawicka M, Lam AK, Paulino C, Dutzler R (June 2018). "Structure of a volume-regulated anion channel of the LRRC8 family". Nature. 558 (7709): 254–259. Bibcode:2018Natur.558..254D. doi:10.1038/s41586-018-0134-y. hdl:11370/47ed7682-8a84-4569-8652-d9687d53667c. PMID 29769723. S2CID 21696249.
  9. ↑ Kefauver JM, Saotome K, Dubin AE, Pallesen J, Cottrell CA, Cahalan SM, et al. (August 2018). "Structure of the human volume regulated anion channel". eLife. 7 e38461. doi:10.7554/eLife.38461. PMC 6086657. PMID 30095067.
  10. ↑ Kasuya G, Nakane T, Yokoyama T, Jia Y, Inoue M, Watanabe K, et al. (September 2018). "Cryo-EM structures of the human volume-regulated anion channel LRRC8". Nature Structural & Molecular Biology. 25 (9): 797–804. doi:10.1038/s41594-018-0109-6. PMID 30127360. S2CID 52047355.
  11. ↑ Jentsch TJ (May 2016). "VRACs and other ion channels and transporters in the regulation of cell volume and beyond". Nature Reviews. Molecular Cell Biology. 17 (5): 293–307. doi:10.1038/nrm.2016.29. PMID 27033257. S2CID 40565653.
  12. ↑ Hyzinski-García MC, Rudkouskaya A, Mongin AA (November 2014). "LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes". The Journal of Physiology. 592 (22): 4855–4862. doi:10.1113/jphysiol.2014.278887. PMC 4259531. PMID 25172945.
  13. ↑ Yamada T, Wondergem R, Morrison R, Yin VP, Strange K (October 2016). "Leucine-rich repeat containing protein LRRC8A is essential for swelling-activated Cl- currents and embryonic development in zebrafish". Physiological Reports. 4 (19) e12940. doi:10.14814/phy2.12940. PMC 5064130. PMID 27688432.
  14. ↑ Okada T, Islam MR, Tsiferova NA, Okada Y, Sabirov RZ (March 2017). "Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR)". Channels. 11 (2). Austin, Tex.: 109–120. doi:10.1080/19336950.2016.1247133. PMC 5398601. PMID 27764579.
  15. ↑ Lutter D, Ullrich F, Lueck JC, Kempa S, Jentsch TJ (March 2017). "Selective transport of neurotransmitters and modulators by distinct volume-regulated LRRC8 anion channels". Journal of Cell Science. 130 (6): 1122–1133. doi:10.1242/jcs.196253. PMID 28193731.
  16. ↑ Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, et al. (December 2015). "Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs". The EMBO Journal. 34 (24): 2993–3008. doi:10.15252/embj.201592409. PMC 4687416. PMID 26530471.
  17. 1 2 Lahey LJ, Mardjuki RE, Wen X, Hess GT, Ritchie C, Carozza JA, et al. (November 2020). "LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP". Molecular Cell. 80 (4): 578–591.e5. doi:10.1016/j.molcel.2020.10.021. PMC 12629894. PMID 33171122.
  18. 1 2 3 Zhou C, Chen X, Planells-Cases R, Chu J, Wang L, Cao L, et al. (May 2020). "Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity". Immunity. 52 (5): 767–781.e6. doi:10.1016/j.immuni.2020.03.016. PMID 32277911.
  19. ↑ Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, et al. (December 2003). "A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans". The Journal of Clinical Investigation. 112 (11): 1707–1713. doi:10.1172/JCI18937. PMC 281644. PMID 14660746.

Further reading