The Cell immunology laboratory at ICGEB Trieste has found a role for actin in the early stages of autoimmunity.
Self-DNA could be recognised as a danger signal by cells. This leads to the activation of immune response toward the cell itself leading to the development of autoimmune diseases. The study published by the Benvenuti lab in JCI Insight shows that cytoskeleton plays a pivotal role in this mechanism.
This principle is well illustrated by Wiskott-Aldrich syndrome, a primary immune deficiency with frequent autoimmune manifestations. These are caused by mutations in a key regulator of cytoskeletal dynamics in immune cells the Wiskott-Aldrich syndrome protein (WASp). The study shows that in Wiskott-Aldrich syndrome mutations in WASp cause errors in actin polimerisation leading also to a slowing down of endo-lysosome movements within the cytosol.
Immune complexes of self-DNA and autoantibodies (DNA-ICs) are ingested by immune cells through endo-lysosomes. Stalling in cytoskeletal dynamics due to mutated WASp releases DNA-ICs from these vesicles within the cytosol. This increases the level of iterferon in the cell leading to the activation of the cGAS/STING sensing pathway. These mechanisms ultimately promote the establishment of the autoimmune reponse.
This finding illustrates a novel role for actin in the regulation of DNA-driven innate responses. This can also provide clues for the management of autoimmune disorders.
Piperno, G.L. et al. 2020. Wiskott-Aldrich syndrome protein restricts cGAS/STING activation by dsDNA immune complexes JCI Insight DOI: 10.1172/jci.insight.132857
You can find a copy of the article in open access here.