Irak4 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.

Whole body loss of Irak4 gives the clearest readout when the question is whether the gene is required at all. Follow up tissue work can still move to a conditional allele if lethality or compensation appears.