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NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases


NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases

Ivona Aksentijevich et al. Front Immunol.


Autoinflammatory diseases are caused by defects in genes that regulate the innate immunity. Recently, the scope of autoinflammation has been broadened to include diseases that result from dysregulations in protein modifications by the highly conserved ubiquitin (Ub) peptides. Thus far these diseases consist of linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. The LUBAC is critical for linear ubiquitination of key signaling molecules in immune response pathways, while deubiquitinase enzymes, OTULIN and TNFAIP3/A20, reverse the effects of ubiquitination by hydrolyzing linear (Met1) and Lys63 (K63) Ub moieties, respectively, from conjugated proteins. Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway. Mutant cells produce elevated levels of many proinflammatory cytokines and respond to therapy with cytokine inhibitors. Patients with an impairment in LUBAC stability have compromised NF-kB responses in non-immune cells such as fibroblasts, while their monocytes are hyperresponsive to IL-1β. Discoveries of germline mutations in enzymes that regulate protein modifications by Ub define a new category of autoinflammatory diseases caused by upregulations in the NF-kB signaling. The primary aim of this review is to summarize the latest developments in our understanding of the etiology of autoinflammation.

Keywords: LUBAC deficiency; OTULIN; TNFAIP3/A20; haploinsufficiency of A20; linear ubiquitin chain assembly complex; otulipenia/otulin-related autoinflammatory syndrome.


Figure 1
Figure 1
Proposed mechanisms of pathogenesis in haploinsufficiency of A20 (HA20), otulipenia/otulin-related autoinflammatory syndrome (ORAS), and linear ubiquitin chain assembly complex (LUBAC) deficiencies. The canonical NF-κB pathway is regulated both by K63 (Lys63)-linked and linear (Met1)-linked ubiquitin (Ub) chains. RIPK1 is the central adaptor for assembly of the TNFR1 receptor signaling complex and is a predominant target for ubiquitination by K63 and linear Ub chains. Polyubiquitylated RIPK1 mediates recruitment of IKK complex that is also target for ubiquitination. The activated IKK complex phosphorylates inhibitor of kappa B (IκBα) and targets IκBα for proteasome-mediated degradation. Linear Ub chains are added to RIPK1 and IKKγ by LUBAC. A20 and OTULIN negatively regulate the NF-κB pathway by cleaving K63 and linear Ub chains from target molecules, RIPK1 and IKKγ. In addition, A20 through its E3 ligase activity adds K48 Ub chains to IKKγ (and TRAF6, not shown in the figure) targeting them for proteasomal degradation. Decreased expression of A20 in patients with HA20 or OTULIN in patients with otulipenia/ORAS will lead to activation of the NF-κB pathway, increased expression of proinflammatory transcripts in immune cells, and systemic inflammation. Decreased expression of LUBAC complex subunits, in patients who carry mutations in HOIP or HOIL-1, results in inhibition of the NF-κB pathway in fibroblasts and B-cells causing immunodeficiency. However, their monocytes hyperproduce proinflammatory cytokines. TNFR1, TNF receptor 1; TRADD, TNFR1-associated death domain protein; RIPK1, the death domain-containing protein kinase receptor-interacting protein1; IKKγ/NEMO, inhibitor of nuclear factor kappa B kinase subunit gamma.
Figure 2
Figure 2
Schematic of the domains and locations of mutations in respective proteins HOIL-1, HOIP, OTULIN, and TNFAIP3/A20. The domains identified are depicted as boxes. The locations of the mutations are indicated with red arrows. (A) HOIL-1 contains the ubiquitin-like (UBL), NPL4 zinc-fingers (NZF) domain, really interesting new gene (RING) domain, and in-between RING (IBR) domain. The mutations are located in UBL and NZF domains. The UBL domain is required for linear ubiquitin chain assembly complex (LUBAC) formation and linear ubiquitination. (B) HOIP has PNGase/UBA or UBX (PUB), zinc finger (ZnF), NZF, ubiquitin-associated (UBA), RING domain, and IBR domain. The homozygous disease-associated mutation is located in the PUB domain that is critical for interaction with OTULIN and stability of LUBAC. (C) OTULIN consists of N-terminal LUBAC-binding PUB-interacting motif (PIM) and C-terminal ovarian tumor (OTU) domain that mediates deubiquitinase (DUB) activity of OTULIN (79–352aa). All three mutations are located in the OTU domain. (D) The DUB activity of A20 is mediated by the OTU domain, and the ZnF domains mediate A20 ubiquitin (Ub) E3 ligase activity, binding to Lys63-linked Ub chains and dimerization. Mutations reported by Zhou at al. are shown on the top of the diagram, while three mutations reported in Japanese patients are shown bellow the diagram. To stay consistent with the Human Genome Variation Society nomenclature the reported p.Gln415fs (35) should be described as p.Lys417Serfs*4. The four nucleotide deletion in the repeat sequence (reported as c.1245_1248del) should be assigned as the most 3′ position in the repeat, i.e., c.1249_1252del; therefore, the proposed nomenclature for the mutation is p.Lys417Serfs*4.
Figure 3
Figure 3
Clinical manifestations of the patients with haploinsufficiency of A20 (HA20) and otulipenia/otulin-related autoinflammatory syndrome. (A) Prominent fat loss (lipodystrophy) and (B) erythematous skin lesions and subcutaneous nodules in a patient with otulipenia. (C) Skin biopsy showed dense inflammatory infiltrate throughout the subcutaneous lobules (right upper corner of the image) and subcutaneous lobular atrophy or lipodystrophy (similar findings have been reported in chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature patients) on the left lower corner of the image. The middle part of the image showed vasculitis affecting a medium-sized artery, characterized by dense intramural and perivascular inflammation with endothelial proliferation and vascular occlusion. Adjacent the affected artery is a medium-sized vein (left lower) showing mild inflammation of the vessel wall. (D) Dermal abscesses in a patient with HA20. (E) Recurrent aphthous (oral) ulcers in a patient with HA20.

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