What is Ubiquitin Family?
Ubiquitin, a small protein in most eukaryotic cells, marks the protein that needs to be broken down and promotes its hydrolysis by proteases. Attachment of ubiquitin to proteins is a key mechanism that determines the timing and strength of many cellular responses. This is because the addition of ubiquitin (ubiquitylation) controls protein longevity, abundance, and function. Ubiquitylation relies on the activities of an ATP-dependent ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3). While the concerted activity of all three proteins is required for modification of substrate proteins with ubiquitin, the E3 has a key role in determining both the timing of substrate ubiquitylation and the type of modification attached.
Signaling Pathway of Ubiquitination:
Ubiquitination of NEMO by the linear ubiquitin chain assembly complex (LUBAC) is essential for activating the canonical NF-κB signaling pathway. NF-κB signaling is activated upon phosphorylation of the inhibitory molecules by the IκB kinase (IKK) complex through either canonical or non-canonical (alternative) pathways. In the canonical pathway, the IKK complex is composed of two catalytic (IKKα and IKKβ) and a regulatory subunit, IKKγ or NF-κB essential modulator (NEMO). Activation of the IKK complex and consequently the NF-κB pathway is contingent upon covalent and non-covalent interactions of NEMO with linear ubiquitin chains.
The ubiquitin (Ub) moiety is recognized by ESCRT-0 and -I subcomplexes. ESCRT-I proteins together with the ESCRTII subcomplex then corral these ubiquitylated transmembrane proteins into membrane domains. Finally, the ESCRT-II subcomplex nucleates the local formation of ESCRT-III co-polymers which, through action of the Vps4 AAA-ATPase, undergo structural changes to drive membrane invagination and scission to release vesicles containing the Ub-marked transmembrane proteins.
Fig 1 The ESCRT (Endosomal Sorting Complex Required for Transport) machinery
Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM (Glioblastoma multiforme). Thus, the UPS represents a potentially valuable target for GBM treatment.
F-box and WD repeat domain-containing 5 (FBXW5), with WD40 repeats, can bind to the PPxY sequence of the large tumor suppressor kinases 1/2 (LATS1/2) kinase domain, resulting in ubiquitination. Ubiquitination and the subsequent degradation of LATS1/2 abrogate the Hippo pathway and worsen gastric cancer (GC).
Fig 2 Schematic of FBXW5 participating in gastric cancer
The study of the signaling pathways of proteins that interact with ubiquitin will help us to find corresponding therapeutic targets for various diseases.