Irak4 Conditional Knockout mouse models

Positioned immediately downstream of MyD88, Irak4 is the mouse ortholog of human IRAK4 and encodes the apical kinase of the Myddosome, using its death domain to assemble a helical oligomer with MyD88 and IRAK1 or IRAK2 and its kinase domain to trigger TRAF6, TAK1, IKK, and MAPK output from all MyD88 coupled TLRs plus IL-1R, IL-18R, and IL-33R. Human IRAK4 deficiency produces narrow but severe susceptibility to pyogenic bacteria that attenuates with age, and MYD88 mutant lymphomas depend on the same complex, providing both loss-of-function and oncology rationales. The decisive allele is the kinase-dead knockin, because it separates catalytic activity from scaffolding and predicts what an active site inhibitor will do, whereas a conditional null predicts the behavior of a heterobifunctional degrader. Add lineage restricted Cre drivers to distinguish myeloid, B cell, and epithelial requirements, and choose humanization when compound selectivity against the human kinase domain is the endpoint.

Tissue restricted knockout of Irak4 keeps wild type function everywhere else. Breeding is often more robust, and the setup mirrors patient biology where mutations arise in a subset of cells.