HPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling and as such is an attractive target for cancer immunotherapy. Although the role of the HPK1 kinase domain (KD) has been extensively characterized, the function of its citron homology domain (CHD) remains elusive. Through a combination of structural, biochemical, and mechanistic studies, we characterize the structure-function of CHD in relationship to KD.

Activation of the Interleukin-18 Signaling Pathway via Direct Receptor Dimerization in the Absence of Interleukin-18.

Interleukin 18 (IL-18) is a key cytokine involved in the activation of T and NK cells, which are major effector cells in tumor killing. However, recombinant IL-18 showed limited efficacy in clinical trials. A recent study showed the lack of efficacy was largely due to the existence of IL-18BP, a soluble decoy receptor for IL-18.

Structure of the core human NADPH oxidase NOX2.

NOX2 is the prototypical member of the NADPH oxidase NOX superfamily and produces superoxide (O), a key reactive oxygen species (ROS) that is essential in innate and adaptive immunity. Mutations that lead to deficiency in NOX2 activity correlate with increased susceptibility to bacterial and fungal infections, resulting in chronic granulomatous disease. The core of NOX2 is formed by a heterodimeric transmembrane complex composed of NOX2 (formerly gp91) and p22, but a detailed description of its structural architecture is lacking.

Antibody targeting of E3 ubiquitin ligases for receptor degradation.

Most current therapies that target plasma membrane receptors function by antagonizing ligand binding or enzymatic activities. However, typical mammalian proteins comprise multiple domains that execute discrete but coordinated activities. Thus, inhibition of one domain often incompletely suppresses the function of a protein.

Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection.

The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.