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Review
. 2015 Sep;67(9):2292-302.
doi: 10.1002/art.39245.

A20-Binding Inhibitor of NF-κB Activation 1 is a Physiologic Inhibitor of NF-κB: A Molecular Switch for Inflammation and Autoimmunity

Rachel T G'Sell  1 , Patrick M Gaffney  2 , David W Powell  1
Affiliations
Review

A20-Binding Inhibitor of NF-κB Activation 1 is a Physiologic Inhibitor of NF-κB: A Molecular Switch for Inflammation and Autoimmunity

Rachel T G'Sell et al. Arthritis Rheumatol. 2015 Sep.
No abstract available

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Conflict of interest statement

Conflict of Interest: None

Figures

Figure 1
Figure 1. Gene and Domain Structure of ABINs
A) Splice variation of TNIP1 yields ABIN1α and ABIN1β isoforms, as a result of alternative splice sites within exon 18. The corresponding colors between the exons in figure A and domains in figure B represent exons that encode known ABIN domains: The ABIN Homology Domains (AHDs) 1–4 and NEMO-Binding Domain (NBD). Exons depicted in grey are translated, but do not encode any known domains. Exons depicted in white remain untranslated. B) Sequence alignment between ABIN1 domains and domains of homologous proteins. The UBD in ABIN proteins and NEMO (UBAN) domain is responsible for ABIN1’s ubiquitin binding function and shares sequence homology with NEMO and the NEMO-like protein, Optineurin. AHD1 and AHD2 are required for A20 binding and NF-κB inhibition, respectively. The roles of AHD3 and AHD4 are not described. Within the aligned sequences, bolded letters represent identical, conserved amino acids. *Mutagenesis (D472N) reported to disrupt ABIN1’s interaction with polyubiquitinated proteins.
Figure 2
Figure 2. Mechanisms of ABIN1-Mediated NF-κB Inhibition
A) A20 dependent mechanism of ABIN-mediated NF-κB inhibition. In this model, ABIN1 acts as an adaptor protein; linking A20 to an active, polyubiquitinated NF-κB mediator protein, such as NEMO. This mechanism of action has been confirmed for NEMO, but simply proposed for NF-κB mediator proteins: RIP1 and IRAK1. Therefore, a question mark follows NF-κB mediator proteins, RIP1 and IRAK1. In this way, ABIN1 facilitates A20’s function as a hydrolase and E3 ligase by mediating the cleavage of K63-linked polyubiquitin and building K48-linked polyubiquitin chains on NF-κB mediator proteins. NF-κB mediator proteins that have had K63-linked ubiquitin cleaved become inactive; resulting in NF-κB inhibition. NF-κB mediator proteins that have had K63-linked ubiquitin cleaved and K48-linked ubiquitin added (dashed red lines) are targeted for degradation in the proteasome; inhibiting NF-κB. B) A20 independent/competitive mechanism of ABIN1-mediated NF-κB inhibition. In this model, ABIN1 competes with NF-κB mediator proteins for polyubiquitin binding. This prevents the ubiquitination and activation of the mediator proteins; inhibiting further NF-κB signaling.
Figure 3
Figure 3. TNIP1 Polymorphisms Associated with Disease
In this schematic of the TNIP1 locus, exons are shown in white, grey and red. White and grey exons represent exons that are untranslated and translated, respectively. The red exon represents the ABIN1 AHD4 coding exon. Single nucleotide polymorphisms (variants) found in the TNIP1 locus and associated to autoimmune and inflammatory diseases are indicated by their reference (rs) number and positioned on the TNIP1 locus (References). The majority of these variants are located up or downstream of the TNIP1 coding regions or in intronic regions.
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References

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    1. Nanda SK, et al. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med. 2011;208:1215–1228. - PMC - PubMed

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