Functions of Linear Ubiquitin Chains in the NF-κB Pathway : Linear Polyubiquitin in NF-κB Signaling.

The ubiquitin conjugation system regulates a wide variety of biological phenomena, in most cases, by modulating protein function via polyubiquitin conjugation. Several types of polyubiquitin chains exist in cells and the type of chain conjugated to a protein seems to determine how the protein is regulated. The polyubiquitin chains that have been reported thus far are generated by conjugation via Lys residues of ubiquitin. We have identified a novel linear polyubiquitin chain, in which the C-terminal Gly of one ubiquitin is conjugated to the α-amino group of the N-terminal Met of another ubiquitin and the ubiquitin ligase complex mediating these reactions specifically generates linear chains. We have shown that linear polyubiquitination is involved in activation of the canonical NF-κB pathway. The regulatory roles of Lys63-linked ubiquitin chains in the NF-κB path way have been extensively studied. In this chapter, we will discuss the distinct roles of linear and K63-linked ubiquitin chains in TNF-α mediated NF-κB activation and the future directions for linear ubiquitin chain research.