CRL4s: the CUL4-RING E3 ubiquitin ligases

Abstract

The evolutionarily conserved cullin family proteins can assemble as many as 400 distinct E3 ubiquitin ligase complexes that regulate diverse cellular pathways. CUL4, one of three founding cullins conserved from yeast to humans, uses a large β-propeller protein, DDB1, as a linker to interact with a subset of WD40 proteins that serve as substrate receptors, forming as many as 90 E3 complexes in mammals. Many CRL4 complexes are involved in chromatin regulation and are frequently hijacked by different viruses. Cullins: the scaffoldThe ubiquitin pathway regulates a wide range of diverse cellular processes by covalently attaching ubiquitin to specific substrate proteins either to alter their functions nonproteolytically or more commonly to promote their degradation by the 26S proteosome [1]. Ubiquitylation begins with the ATP dependent activation of ubiquitin by the E1 enzyme, and is followed by the subsequent transfer of ubiquitin to an E2 ubiquitin conjugating enzyme, and finally an E3 ubiquitin ligase is responsible for recognizing a specific substrate and promoting ubiquitin ligation. Over a thousand distinct E3 ligases, belonging to two major families, the HECT family and the RING family, are present in higher eukaryotes. Human cells contain as many as 28 HECT proteins and most, if not all, are believed to function as E3 ligases. More than 450 RING proteins are expressed in human cells and E3 ligase activity has been experimentally demonstrated for many of them.Although not containing a RING domain themselves, members of the evolutionarily conserved cullin family can bind with a small RING protein, either ROC1 or ROC2 (for RING of Cullins; also known as Rbx and Hrt1), to constitute a large family of cullin-RING E3 ligases (CRLs). There are three cullins in yeast, six in Caenorhabditis elegans and Drosophila melanogaster (CUL1-6), up to nine in Arabidopsis thaliana, and six in humans (CUL1, 2, 3, 4A, 4B and 5). In addition, three other proteins, CUL7 and CUL9 (also known as PARC) in mammals and APC2 (anaphase promoting complex subunit 2) in all eukaryotes, contain significant sequence homology to cullins over a ~180 residue region and bind ROC or a homologous small RING protein, APC11. Unlike other RING E3 ligases, cullins do not bind substrates directly, but rather rely on substrate recruiting receptors that are typically joined to the cullin complex by a linker protein (Fig. 1). Remarkably, each cullin can associate with a different family of substrate receptors, leading to the assembly of as many as 400 distinct CRLs. A recent estimate suggests that 20% of all proteins subject to proteasomal degradation are targeted by CRLs [2].Corresponding author: Xiong, Y. (yxiong@email.unc.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable ...

The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2

“…More recently, Skp2 has been shown to exhibit homeostatic regulation of tumor suppressor DAB2IP and suppression of JARID1B demethylase activity in prostate carcimona. 33,34 Likewise cullin1 based E3 ubiquitin ligases, cullin4-based E3 ubiquitin ligases also play an important role in cell proliferation, DNA damage repair 7 and ubiquitylation of histone 10 via different DCAFs like Cul4-DDB1-Det1-Cop1 regulate intracellular c-jun level. 35 The present study showed that TRUSS expression peaked during the G1 phase of cell cycle and as the cells progress from G1 to S phase TRUSS level gets down-regulated coinciding with Skp2 expression.…”

“…7 Viruses not only regulate the host-encoded E3 ligases but also encode their own Ub ligases in order to exploit the cellular homeostasis. [36][37][38][39][40] The viral HBx oncoprotein which is implicated in hepatocellular carcinoma (HCC), 41 is also known to regulate the proteasomal functions.…”

“…Recent studies on CRL4s have suggested over 50 different substrate recognition components or DCAFs. [7][8][9][10][11] Tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein is one of the DCAFs known to regulate c-Myc are well known to be overexpressed in several hematological and solid tumors. Though, deregulated expression of TRUSS has been observed in many cancers, 12 very little is known about its other cellular targets and functions.…”

CUL4B ubiquitin ligase in mouse development: A model for human X-linked mental retardation syndrome?

“…CUL4 is a member of the cullin-RING ubiquitin ligase family, the largest E3 ligase family, which appears to account for ~20% of total protein degradation by the ubiquitin-proteasome system [1][2][3]. CUL4 is conserved during evolution from yeast to human.…”

“…In yeast, CUL4 encodes a single gene, but mammalian cells express two closely related paralogs, CUL4A and CUL4B with about 82% sequence identity. CUL4A and CUL4B assemble structurally similar E3 complexes through binding to an adaptor protein (DDB1) and a substrate receptor protein (DCAF) at the N-terminus, and a RING protein RBX1 at the C-terminus (Figure 1), and share functional redundancy in targeting substrates such as p21 and Cdt1 for ubiquitination and degradation [1,2]. The Cul4a-null mice are viable and display no abnormal development and growth phenotypes, likely due to functional compensation from Cul4b [4,5].…”