Mendelian diseases of dysregulated canonical NF-κB signaling: From immunodeficiency to inflammation

Abstract

NF-B is a master transcription factor that activates the expression of target genes in response to various stimulatory signals. Activated NF-B mediates a plethora of diverse functions including innate and adaptive immune responses, inflammation, cell proliferation, and NF-B is regulated through interactions with I B inhibitory proteins, which are in turn regulated by the inhibitor of B kinase (IKK) complex. Together, these 3 components form the core of the NF-B signalosomes that have cell-specific functions which are dependent on the interactions with other signaling molecules and pathways. The activity of NF-B pathway is also regulated by a variety of post-translational modifications including phosphorylation and ubiquitination by Lys63, Met1, and Lys48 ubiquitin chains. The physiologic role of NF-B is best studied in the immune system due to discovery of many human diseases caused by pathogenic variants in various proteins that constitute the NF-B pathway. These disease-causing variants can act either as gain-of-function (GoF) or loss-of-function (LoF) and depending on the function of mutated protein, can cause either immunodeficiency or systemic inflammation. Typically, pathogenic missense variants act as GoF and they lead to increased activity in the pathway. LoF variants can be inherited as recessive or dominant alleles and can cause either a decrease or an increase in pathway activity. Dominantly inherited LoF variants often result in haploinsufficiency of inhibitory proteins. Here, we review human Mendelian immunologic diseases, which results from mutations in different molecules in the canonical NF-B pathway and surprisingly present with a continuum of clinical features including immunodeficiency, atopy, autoimmunity, and autoinflammation.

Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC

“…Cpdm mice with global SHARPIN deletion exhibit multiorgan inflammation and severe dermatitis, which can be partially alleviated with β1-integrin inhibition in vivo 38 but is primarily driven by LUBAC destabilization, reduced NF-κB activation, and diminished protection against tumor necrosis factor (TNF)-α–induced apoptosis. 39 To examine LUBAC function in platelets, we performed western blots with lysate from platelets stimulated with a cocktail of agonists. In contrast to a time-dependent increase in Met-1 ubiquitination observed upon agonist stimulation of SHARPIN-replete platelets, SHARPIN-null platelets exhibited substantially lower levels of Met-1 ubiquitination, both before and after agonist stimulation ( Figure 5A ).…”

Disorders of ubiquitylation: unchained inflammation

“…NF-κB is a transcription factor that lies at the centre of multiple innate and adaptive immune pathways 78 . NF-κB has both canonical and non-canonical pathways that regulate activation of immune responses 79 .…”

“…Pathogenic variants of proteins that are involved in NF-κB pathways can behave either as gain-of-function or as loss-of-function alleles and, depending on the affected domain and the function of the altered protein, can cause either immunodeficiency or systemic inflammation. Nevertheless, all the diseases resulting from disruption of NF-κB pathways present with a continuum of clinical features, including immunodeficiency, autoinflammation, autoimmunity and atopy 78 . A strong additional piece of evidence comes from identification of an autoinflammatory disease caused by haploinsufficiency of RELA (encoding a subunit of NF-κB) 82 , which has overlapping clinical features with the disease caused by dysregulated ubiquitylation, termed haploinsufficiency of A20 (HA20; A20 is encoded by TNFAIP3 ).…”

Master regulator genes and their impact on major diseases

“…Master regulator gene Functions TGF-β signaling pathway TGF-β signaling pathway master regulator of the respiratory system, epithelialmesenchymal transition and metastasis, and cancer development, etc (Fazilaty et al, 2013;Solomon et al, 2010;Zhou et al, 2014) PI3K-AKT-mTOR signaling pathway PI3K-AKT-mTOR signaling pathway master regulator of cancer (Xia & Xu, 2015) Hedgehog (Hh) signaling pathway Hedgehog (Hh) signaling pathway master regulator of cell differentiation (Peng & Joyner, 2015) NF-kappaB signaling pathway NF-kappaB signaling pathway master regulator of innate immunity and inflammatory signaling (Krappmann et al, 2004;Matroule, Volanti & Piette, 2006;Schnappauf & Aksentijevich, 2020;Zeitz et al, 2017) Wnt Kang, 2010;Schönenberger & Kovacs, 2015;Xiao, 2015;Zhao et al, 2020) tissue/organ specificity, among which SCL/TAL1, VEGF, and PU.1 are the MRGs of hematopoiesis; Sim1 and Gcm are the MRGs of Drosophila neurodevelopment; FOXM1, Blimp1, Oct4, and Myc are the MRGs that regulate the cell cycle, B-cell differentiation to plasma cells, embryonic stem cells, and cell performance, respectively; CTCF is the MRG of human epigenetic and genomic spatial tissue; and FOXj1 is the MRG of the ciliary formation program. In bacteria, the MRGs include SinR, CtrA, FlhDC, Fur, CsgD, Spo0A, CcpA, LuxR, and WOR1.…”