![]() "SRSF2 can be a potential target for managing Wiskott-Aldrich syndrome disease," says the other co-first author and Ph.D. In stem cell–derived immune cells, for example, knocking down expression of this splicing factor helped prevent the release of inflammation-promoting molecules, a finding that raises tantalizing therapeutic possibilities. Notably, though, WASP deficiencies could be overcome by genetically targeting the activity of SRSF2. "Our study reveals for the first time that WASP is a phase-separated protein that can directly participate in the process of RNA splicing," says co-first author and Ph.D. Known as biomolecular condensates, these subcellular hubs normally contain WASP alongside DNA-to-RNA copying enzymes, newly synthesized gene transcripts and splicing factors including SRSF2. The team went on to show that WASP is needed to constrain the activity of SRSF2 through the production of transient liquid-like clusters of proteins and nucleic acids. In collaboration with bioengineer Samir Hamdan and his lab group, the researchers then showed that an operational version of WASP works together with a particular splicing factor, SRSF2. General protein function suffers, and the cell becomes unwell. Multipotent cells can develop into more than one cell type, but are more limited than pluripotent. Pluripotent cells can give rise to all of the cell types that make up the body embryonic stem cells are considered pluripotent. Pluripotent stem cells are cells that have the capacity to self-renew by dividing and to develop into the three primary germ cell layers of the early embryo and therefore into all cells of the. With such high levels of these splicing factors, transcripts often get truncated or end up with missing domains. Embryonic cells within the first couple of cell divisions after fertilization are the only cells that are totipotent. They found that cells without a working version of WASP had elevated levels of another group of proteins known as RNA splicing factors, which play a critical role in processing gene transcripts so that they encode the proper recipe. The stem cells and their differentiated progeny allowed the researchers to study the consequences of aberrant WASP activity in different immune cell lineages. "These are powerful models that can help us understand WASP functions and the disease mechanisms of Wiskott-Aldrich syndrome in an authentic human cellular context," says Li. They also used gene editing to either fix the mutational error of patient iPSCs or delete the entire WAS gene of a WT iPSC line, resulting in paired stem cell lines that matched in all ways except in their WAS gene sequence. To better understand what WASP does, stem cell biologist Mo Li and his KAUST colleagues teamed up with collaborators from the Salk Institute for Biological Studies in California, U.S., and created a panel of induced pluripotent stem cells (iPSCs) from patients with the immunological deficiency. It has been known for almost 30 years that mutations in the gene that encodes WASP-Wiskott–Aldrich syndrome protein-cause the immune abnormality, but the precise functions of this protein have long eluded scientists. WAS afflicts around one in every 100,000 babies, causing frequent bleeding episodes and infections while also elevating the risk of life-threatening inflammatory diseases and certain cancers.
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