Coordinated regulation of scaffold opening and enzymatic activity during CARD11 signaling

Abstract

The activation of key signaling pathways downstream of antigen receptor engagement is critically required for normal lymphocyte activation during the adaptive immune response. CARD11 is a multidomain signaling scaffold protein required for antigen receptor signaling to NF-B, c-Jun N-terminal kinase, and mTOR. Germline mutations in the CARD11 gene result in at least four types of primary immunodeficiency, and somatic CARD11 gain-of-function mutations drive constitutive NF-B activity in diffuse large B cell lymphoma and other lymphoid cancers. In response to antigen receptor triggering, CARD11 transitions from a closed, inactive state to an open, active scaffold that recruits multiple signaling partners into a complex to relay downstream signaling. However, how this signal-induced CARD11 conversion occurs remains poorly understood. Here we investigate the role of Inducible Element 1 (IE1), a short regulatory element in the CARD11 Inhibitory Domain, in the CARD11 signaling cycle. We find that IE1 controls the signal-dependent Opening Step that makes CARD11 accessible to the binding of cofactors, including Bcl10, MALT1, and the HOIP catalytic subunit of the linear ubiquitin chain assembly complex. Surprisingly, we find that IE1 is also required at an independent step for the maximal activation of HOIP and MALT1 enzymatic activity after cofactor recruitment to CARD11. This role of IE1 reveals that there is an Enzymatic Activation Step in the CARD11 signaling cycle that is distinct from the Cofactor Association Step. Our results indicate that CARD11 has evolved to actively coordinate scaffold opening and the induction of enzymatic activity among recruited cofactors during antigen receptor signaling.

Genetic profile of adult T‐cell leukemia/lymphoma in Okinawa: Association with prognosis, ethnicity, and HTLV‐1 strains

“…Reproducible results in the two independent cohorts in Okinawa and mainland Japan indicated the crucial cooperative roles of PRKCB and CARD11 mutations in the pathogenesis of ATLL. Previous studies also described the importance of intragenic focal deletions in the inhibitory domain of CARD11 , which cause CARD11 to be constitutively active 19,34 . However, these small deletions were not detected in the present study owing to the resolution of the SNP array, which is one of the limitations in this study.…”

“…Previous studies also described the importance of intragenic focal deletions in the inhibitory domain of CARD11, which cause CARD11 to be constitutively active. 19,34 However, these small deletions were not detected in the present study owing to the resolution of the SNP array, which is one of the limitations in this study.…”

The LUBAC participates in lysophosphatidic acid-induced NF-κB activation

“…The CBM complex is an essential gateway for transducing NF-κB signaling downstream of antigen receptors and GPCRs [8]. In T and B lymphocytes, the CBM complex recruits the LUBAC to facilitate the optimal activation of NF-κB [14][15][16][17]. However, the situation in nonimmune cells remains unknown.…”

“…Recently, we and others reported that the linear ubiquitin assembly chain complex (LUBAC) is dynamically recruited to the CBM following antigen receptor ligation and participates in IKK/NF-κB activation [14][15][16][17]. This triad composed of the E3 ligases HOIP (also known as RNF31), HOIL1 (also known as RCBK1) and the adaptor SHARPIN catalyzes linear ubiquitin chains and conveys NF-κB signaling downstream a variety of immunoreceptors [18].…”

Mechanistic impact of oligomer poisoning by dominant-negative CARD11 variants

“…In resting B and T lymphocytes, CARD11 is kept in a closed, inactive state owing to the cooperative autoinhibitory action of four repressive elements (REs) within the Inhibitory Domain that function with redundancy to prevent the association of cofactors, in part through intramolecular interactions with other CARD11 domains ( Jattani et al., 2016a ; 2016b ). Upon antigen receptor triggering, CARD11 activity is induced through several defined steps in the CARD11 signaling cycle ( Wang et al., 2019 ). First, in a poorly understood Opening Step, the inhibitory REs are neutralized and CARD11 converts to an open, active state in which surfaces of CARD and Coiled-coil domains become exposed and available for binding proteins in trans .…”