Abstract Kindlins are adaptor proteins that function synergistically with talin to activate integrins, facilitating cell adhesion and migration. In addition to this role, kindlins have other functions. In immune cells, kindlin-3 is the predominant kindlin paralog. Loss of kindlin-3 due to gene mutations leads to a bleeding disorder and impaired immune function, as observed in patients with leukocyte adhesion deficiency type III (LAD-III). In this study, we demonstrate that kindlin-3 maintains IL-2Rβ at the plasma membrane, a process that relies on the integrin LFA-1. This retention supports IL-2 signaling and helps protect natural killer (NK) cells from apoptosis when IL-2 levels are low. Kindlin-3 also promotes the colocalization of integrin LFA-1 and IL-2Rβ at sites where LFA-1 engages its ligand. Mechanistically, kindlin-3 directly binds the cytoplasmic domain of the interleukin-2 receptor β chain (IL-2Rβ) via its F0 subdomain. This interaction specifically targets a membrane-distal region of IL-2Rβ (residues 530–551) with micromolar affinity. Therefore, kindlin-3 acts as a bridging molecule that connects IL-2Rβ to the integrin LFA-1, thereby potentially coordinating cell adhesion with cytokine signaling.
Teng et al. (Fri,) studied this question.