Linear Polyubiquitination: A Crucial Regulator of NF-κB Activation

Abstract

NF-κB is a transcription factor known to be involved in pleomorphic biological phenomena such as infl ammation and immune responses. Abnormal activation of NF-κB has been reported in many pathological conditions, including malignant tumors. Therefore, the NF-κB activation pathway has been extensively studied and involvement of the ubiquitin conjugation system in the NF-κB activation pathways has been revealed. Although the ubiquitin conjugation system was discovered as a part of a protein degradation pathway, non-degradable roles of the ubiquitin system have been revealed recently. Several types of polyubiquitin chains exist in cells and the type of chain seems to determine how ubiquitinated proteins are regulated. We have identifi ed that a new type of polyubiquitin chain, the linear polyubiquitin chain, plays a crucial role in regulating the NF-κB activation pathway in non-degradable manner. In this chapter, the discovery, roles in NF-κB activation, and involvement in the pathogenesis of cancers of linear ubiquitination will be discussed. Keywords NF-κB • Ubiquitin • LUBAC • Linear ubiquitin chain • cpdm • B cell lymphoma The Ubiquitin Conjugation SystemThe ubiquitin system, which is one of the most extensively studied post-translational protein modifi cation systems, has been identifi ed as part of an energy-dependent degradation system [ 1 ]. Ubiquitin is a protein-based modifi er composed of 76 amino acids. Through the function of three enzymes called the ubiquitin-activating enzyme (E1), the ubiquitin conjugating enzyme (E2) and the ubiquitin ligase (E3), ubiquitin is conjugated to the substrate proteins that are recognized by E3s. Ubiquitin is added onto ubiquitin pre-conjugated to the substrates to generate polyubiquitin chains-polymer of ubiquitin. The proteasome recognizes the polyubiquitin chains

Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

“…Emerging experiments have shown that incorrect regulation of cellular processes (either tumour inhibitors or promoters) contributes to cancer pathogenesis and progression ( Shirane et al, 1999 ). Additionally, the cellular functions of atypical ubiquitin linkages (except Lys11-linked ubiquitin) are supposed to be non-degradable ( Kulathu and Komander, 2012 ; Iwai, 2014 , 2015 ; Meza Gutierrez et al, 2018 ) and in most cases, activities involved in Lys63-linked poly-ubiquitin chains are also considered to be non-degradable ( Liu et al, 2015 ).…”