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2’3’-cGAMP binds and activates Rab18 to promote cell migration

ABSTRACT: 2’3’-cGAMP binds and activates Rab18 to promote cell migration

PROVIDER: PRJNA865774 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20810709_1.fastq.gz	Fastqsanger.gz
	SRR20810709_2.fastq.gz	Fastqsanger.gz
	SRR20810710_1.fastq.gz	Fastqsanger.gz
	SRR20810710_2.fastq.gz	Fastqsanger.gz
	SRR20810711_1.fastq.gz	Fastqsanger.gz

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2’3’-cGAMP binds and activates Rab18 to promote cell migration

Project description:Cyclic dinucleotides serve as bacterial secondary messengers regulating sporulation, motility, biofilm formation and virulence. A nonsymmetric c-di-GAMP is firstly identified in bacteria to promote colonization, while mammalian 2’3’-cGAMP is synthesized by cGAS through binding and activating STING to trigger innate immune activation. However, pathophysiological function of 2’3’-cGAMP beyond innate immunity remains elusive. Here, we report 2’3’-cGAMP facilitates cell migration independent of STING and its innate immune function. 2’3’-cGAMP interactome analysis with a targeted shRNA-screen identifies the GTPase Rab18 as a direct 2’3’-cGAMP binding partner and effector in cell migration control. Mechanistically, 2’3’-cGAMP binds Rab18-S17, E36 and R92 residues to facilitate Rab18 activation and subsequently promotes FosB transcription in promoting cell migration. Low-dose doxorubicin induces 2’3’-cGAMP synthesis and facilitates cell migration in vitro and in vivo. Interestingly, lovastatin induces Rab18 phosphorylation abolishes 2’3’-cGAMP recognition to antagonize 2’3’-cGAMP induced cell migration. Together, our study reveals a novel 2’3’-cGAMP function in cell migration control beyond innate immunity via binding Rab18 that provides new insights into clinical applications of 2’3’-cGAMP.

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Viruses antagonise expression and function of cGAMP transporters, channels and pores

Project description:DNA sensing is a fundamental process in the immune system, including host defence against viruses. The DNA sensor cGAS synthesises 2’3’ cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which subsequently induces innate immunity. cGAMP not only activates STING in the cell where it is produced but also transfers to other cells. Transporters, channels and pores including SLC19A1, the SLC46A family, P2X7, ABCC1 and volume-regulated anion channels (VRACs) release cGAMP into the extracellular space and/or import cGAMP into cells. Emerging evidence suggests these proteins are important in antiviral immunity. Here, we investigated whether viruses antagonise cGAMP transporters, channels and pores. We report that infection with multiple human viruses depleted cGAMP conduits from cells. This included herpes simplex virus 1 (HSV-1) that targeted the VRAC subunits LRRC8A and LRRC8C, as well as SLC46A2 and P2X7, for degradation. The HSV-1 protein UL56 was required and sufficient for these effects that were mediated at least partially by proteasomal turnover. UL56 thereby inhibited the cGAMP uptake via VRAC, SLC46A2 and P2X7. Taken together, we show that HSV-1 actively antagonises cGAMP transfer across the plasma membrane and propose this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.

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