The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

Lahey, L. J.; Wen, X.; Mardjuki, R. E.; Böhnert, V.; Ritchie, C.; Carozza, J. A.; Hess, G. T.; Maduke, M.; Bassik, M. C.; Li, L.

doi:10.1101/2020.02.13.948273

bioRxiv · 10.1101/2020.02.13.948273

The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells

Lahey, L. J.·Wen, X.·Mardjuki, R. E.·Böhnert, V.·Ritchie, C.·Carozza, J. A.·Hess, G. T.·Maduke, M.·Bassik, M. C.·Li, L.

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Abstract

Extracellular 23-cyclic-GMP-AMP (cGAMP) is an immunotransmitter secreted by cancer cells and taken up by host cells to activate the anti-cancer STING pathway. No cGAMP exporter has been identified, and SLC19A1, a recently identified cGAMP importer, does not account for the import activity in most cell types. Here, we identify the LRRC8A:C heteromeric channel, a volume-regulated anion channel (VRAC), as a cGAMP transporter. This channel mediates cGAMP import or export depending on the cGAMP chemical gradient, and channel activation or inhibition modulates cGAMP transport. Other 23-cyclic dinucleotides are also transported by LRRC8A:C channels, including the investigational cancer therapeutic ADU-S100. Furthermore, we demonstrate that the LRRC8A-containing channel is the dominant cGAMP importer in primary human vasculature cells. Given tumor vasculatures regulation of immune infiltration and its disruption in response to STING agonists, we have uncovered a leading molecular mechanism for extracellular cGAMP signaling in this important anti-cancer target.

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Lahey, L. J., Wen, X., Mardjuki, R. E., Böhnert, V., Ritchie, C., Carozza, J. A., Hess, G. T., Maduke, M., Bassik, M. C., Li, L.. 2020-02-14. The LRRC8A:C Heteromeric Channel Is a cGAMP Transporter and the Dominant cGAMP Importer in Human Vasculature Cells. https://doi.org/10.1101/2020.02.13.948273

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