RBCK1 gene

The RBCK1 gene, (RBCK1 stands for: RanBP-Type And C3HC4-Type Zinc Finger-Containing Protein 1) is a protein coding gene localized on chromsome 20p13. The signaling pathways affected include TNF signaling and class I MHC-mediated antigen processing and presentation.

The RBCK1 gene encodes an E3 ubiquitin-protein ligase that accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, such as UBE2L3/UBCM4, and then transfers it to substrates (Yamanaka K et al. (2003). The enzyme functions as an E3 ligase for oxidized IREB2 and both heme and oxygen are required for IREB2 ubiquitination (Tian Y et al. 2007). The RBCK1 protein, also known as HOIL1, promotes the ubiquitination of TAB2 and IRF3 and their degradation by the proteasome. The enzyme is a component of the LUBAC complex, which conjugates linear ('Met-1'-linked) polyubiquitin chains to substrates and plays a key role in the activation of NF-kappa-B and the regulation of inflammation (Gerlach B et al. 2011). LUBAC conjugates linear polyubiquitin to IKBKG and RIPK1 and is involved in the activation of the canonical NF-kappa-B and JNK signaling pathways. Linear ubiquitination mediated by the LUBAC complex interrupts TNF-induced cell death and thereby prevents inflammation (Gerlach B et al. 2011). LUBAC is recruited to the TNF-R1 signaling complex (TNF-RSC) after polyubiquitination of TNF-RSC components by BIRC2 and/or BIRC3 to conjugate linear polyubiquitin to IKBKG and possibly other components that contribute to the stability of the complex (Gerlach B et al. 2011).

The LUBAC complex is also involved in innate immunity by conjugating linear polyubiquitin chains to the surface of bacteria that enter the cytosol to form the ubiquitin envelope that surrounds the bacteria (Noad J et al. 2017). LUBAC is not able to initiate the formation of the bacterial ubiquitin coat, but can only promote the formation of linear polyubiquitins on pre-existing ubiquitin. The bacterial ubiquitin coat acts as an "eat-me" signal for xenophagy and promotes the activation of NF-kappa-B. Together with OTULIN, the LUBAC complex regulates canonical Wnt signaling during angiogenesis. Binds polyubiquitin of different binding types.

In summary, the HOIL1 enzyme protein enables multiple functions, including identical protein binding activity, protein sequestration and ubiquitin binding activity. Involved in multiple processes, including T cell receptor signaling, cellular protein metabolism and regulation of DNA-binding transcription factor activity. Part of the LUBAC complex. Involved in glycogen storage disease.

Diseases associated with RBCK1 include:

• HOIL-1 deficiency syndrome

In 2012, Boisson et al. (2012) described three children who developed very early recurrent fever episodes with a strong acute phase reaction, hepatosplenomegaly and lymphadenopathy. Serositis or inflammatory dermatoses, which are usually found in autoinflammatory diseases, were absent. All children were abnormally susceptible to bacterial infections, two out of three also to viral infections. The polysaccharide response to ^Pneumovax® was impaired. The overall clinical picture was thus characterized by immunodeficiency and autoinflammation. In addition, all three children had amylopectin-like intracellular deposits in the heart, smooth and skeletal muscles, which in combination defined a new clinical picture.

1. Boisson B et al. (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inheriteHOIL-1 and LUBAC deficiency. Nat Immunol 13):1178-1186
2. Gerlach B et al. (2011) Linear ubiquitination prevents inflammation and regulates immune signaling. Nature 471:591-596.
3. Noad J et al. (2017) LUBAC-synthesized linear ubiquitin chains restrict cytosol-invading bacteria by activating autophagy and NF-κB. Nat Microbiol 2:17063.
4. Tian Y et al. (2007) RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation. J Biol Chem 282:16776-16782.
5. Yamanaka K et al. (2003) Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2. Nat Cell Biol 5:336-340.