When mad AIOLOS drags IKAROS down: a new pathogenic mechanism

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The transcription factors IKAROS and AIOLOS (which bear the name of the characters of Greek mythology) regulate the development of lymphocytes. According to Greek mythology, Ikaros had wings that were of feathers and wax; one day, it flew too close to the sun and its wings melted, causing it to fall and die later. Aiolos, on the other hand, was a god of the wind and, by order of the higher-ranking gods, carried violent and stormy winds to cause devastation and despair. In this work of art, the mutant Aiolos loses control and power over stormy winds and chaos. The work illustrates the fallen Ikaros not due to being very close to the sun, but to the result of having been impressed by the mutant Aiolos. Credit: Department of Pediatrics and Developmental Biology, TMDU

Primary immunodeficiencies, such as severe combined immunodeficiency disease (SCID), occur when the immune system does not function properly, leading to increased sensitivity to various infections, autoimmunity, and cancers. Most of these are inherited and have underlying genetic causes. A TMDU team has identified a new disorder resulting from a mutation in a protein called AIOLOS, which works through a previously unknown pathogenic mechanism called heterodimeric interference.

He known as IKAROS zinc finger proteins (IKZFs) is associated with the development of lymphocytes, a type of white blood cell involved in the It means that mutations may be involved in this family deficiencies. To date, most research has focused on the IKAROS protein, encoded by the IKZF1 gene, although it is the basis whereby the IKAROS mutations cause the deficiencies is not yet fully understood. It has also been shown that a mutation in AIOLOS — another member of the IKZF family that is encoded by the IKZF3 gene — causes an inherited immune deficiency. In addition to not functioning properly on its own, the resulting mutant protein interferes with the functioning of the IKAROS protein.

TMDU researchers discovered this new mechanism while investigating the cause of a hereditary B-cell deficiency previously described observed in a family of patients. After sequencing all the genes encoding the proteins, the team focused their research on AIOLOS, as IKAROS is known to be the cause of B cell deficiency. They showed that the mutant form of AIOLOS that there was in this family not only did it not work, but it was actively linked to a DNA sequence different from the normal version of the protein.

They continued to use a mouse model harboring an equivalent AIOLOS mutation identified in patients to outline the underlying pathogenic mechanism. AIOLOS and IKAROS join to form a “heterodimer”. The mutant form of AIOLOS retained the ability to bind IKAROS, but interfered with the normal function of IKAROS and caused the heterodimer to be recruited to the incorrect regions of the genome.

When mad AIOLOS drags IKAROS down: a new pathogenic mechanism

AIOLOS forms a heterodimer with its partner IKAROS. They comprise a complex of transcription factors that regulate the genes involved in lymphocyte development. In patients and the mouse model that mimics the patient, mutant AIOLOS forms heterodimerally with IKAROS and interferes with its function by blocking AIOLOS-IKAROS junctions at their physiological binding sites and sequestering IKAROS at non-physiological junction regions in shape. of heterodimers. Credit: Department of Pediatrics and Developmental Biology, TMDU

“This is a new pathogenic mechanism we call heterodimeric interference,” says lead author Motoi Yamashita, “where a mutant protein in a heterodimer hijacks the function of the normal partner protein.”

The team was able to rescue part of the immune function of the mouse model by eliminating the dimerization domain of the AIOLOS mutant.

“Being able to rescue the phenotype in our indicates a potential therapeutic approach, “says Tomohiro Morio, lead author.” Suppression of the domain responsible for binding IKAROS in the AIOLOS mutant could improve the immunodeficiency observed in patients “.

The discovery of this new pathogenic mechanism, heterodimeric interference, may help shed light on many other disease processes such as autoimmunity and the development of cancer, where mutant proteins act in the same way.


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More information:
Motoi Yamashita et al, a variant in human AIOLOS impaired adaptive immunity by interfering with IKAROS, Immunology of nature (2021). DOI: 10.1038 / s41590-021-00951-z

Provided by Tokyo Medical and Dental University

Citation: When Crazy AIOLOS Drags IKAROS Down: A New Pathogenic Mechanism (2021, July 16) Retrieved July 17, 2021 at https://medicalxpress.com/news/2021-07-mad-aiolos-ikaros-pathogenic- mechanism.html

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