Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes

Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control?

“…Control of peripheral membrane structures has been attributed to N-WASp, WASp, WAVE, and WHIMP, whereas WASH, JMY, and WHAMM were associated with ER-Golgi and endosome trafficking. Compatibly with its abundance and the poor expression of the other NPFs, WASp was shown to multitask at the cell periphery and intracellularly in immune cells ( 80 , 118 ). WASp regulates multiple immune cell functions, ranging from BCR and TCR receptor signaling in lymphocytes to migration and phagocytosis in myeloid cells ( 81 ).…”

“…Interestingly, stalling in maturation-defective organelles facilitated leakage of DNA-ICs into the cytosol, inducing activation of the STING pathway. Genetic deletion of STING corrected excessive responses of WASp null cells, uncovering cytosolic DNA sensing as a contributor of innate immune dysregulation in WAS ( 118 ). Building on this pilot discovery, we hypothesize that WASp may control cGAS-STING mediated IFN-I production by mechanisms beyond endosomal maturation and integrity such as STING trafficking at the ER-Golgi, post-Golgi transfer, and autophagosomal degradation ( 80 , 118 ) ( Figure 2 ).…”

“…Genetic deletion of STING corrected excessive responses of WASp null cells, uncovering cytosolic DNA sensing as a contributor of innate immune dysregulation in WAS ( 118 ). Building on this pilot discovery, we hypothesize that WASp may control cGAS-STING mediated IFN-I production by mechanisms beyond endosomal maturation and integrity such as STING trafficking at the ER-Golgi, post-Golgi transfer, and autophagosomal degradation ( 80 , 118 ) ( Figure 2 ). Moreover, by interacting with phosphoinositides ( 128 ), WASp may participate in cGAS anchoring at the plasma membrane, a mechanism that prevents recognition of cytosolic self-DNA in myeloid cells ( 129 ).…”

Macrophage SCAP Contributes to Metaflammation and Lean NAFLD by Activating STING–NF-κB Signaling Pathway

“…Upon activation, STING translocates from the ER to the Golgi, where it recruits TBK1 and then activates the NF-κB signaling pathway, driving the release of inflammatory factors. 32 , 42 , 43 Coincidentally, the Golgi is also an important platform for the biological function of SCAP, where it is involved in the cleavage activation of SREBPs and the maintenance of cholesterol homeostasis. 26 This suggests the possible interaction of SCAP with STING, and our extensive data provide ample evidence for this possibility.…”

Molecular Tuning of Actin Dynamics in Leukocyte Migration as Revealed by Immune-Related Actinopathies

“…However, given the fact that proteins such as WASP regulate endosome trafficking ( 177 ), it would be interesting to further investigate the possible contribution of vesicle trafficking to the actinopathy-associated cell motility defects.…”