SUMO-targeted ubiquitin ligases

Sriramachandran, Annie M.; Dohmen, R. Jürgen

doi:10.1016/j.bbamcr.2013.08.022

Cited by 215 publications

(245 citation statements)

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“…The SUMOtargeted E3 ubiquitin ligase (STUbL) family of proteins mediates crosstalk between ubiquitin and SUMO. STUbL-dependent ubiquitination of SUMO conjugated target proteins, coupled or not with target degradation at the proteasome, drives key processes in the maintenance of genome stability [20][21][22][23]. The human STUbL RNF4 was recently demonstrated to act directly in DSB repair, by targeting multiple sumoylated proteins including MDC1, 53BP1 and BRCA1 [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

et al. 2014

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The post-translational modification of DNA repair and checkpoint proteins by ubiquitin and small ubiquitin-like modifier (SUMO) critically orchestrates the DNA damage response (DDR). The ubiquitin ligase RNF4 integrates signaling by SUMO and ubiquitin, through its selective recognition and ubiquitination of SUMO-modified proteins. Here, we define a key new determinant for target discrimination by RNF4, in addition to interaction with SUMO. We identify a nucleosome-targeting motif within the RNF4 RING domain that can bind DNA and thereby enables RNF4 to selectively ubiquitinate nucleosomal histones. Furthermore, RNF4 nucleosome-targeting is crucially required for the repair of TRF2-depleted dysfunctional telomeres by 53BP1-mediated non-homologous end joining.

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Section: Introductionmentioning

confidence: 99%

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

et al. 2014

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“…Some viral proteins function as a SUMO E3 ligase, including the Ad5 E1B-55K protein (16,17) for p53 sumoylation and Kaposi's sarcoma-associated herpesvirus (KSHV) KbZIP (18) for sumoylation of p53 and the retinoblastoma protein. Recent studies have demonstrated that poly-SUMO2/3 chains serve as a ubiquitination signal for SUMO-targeted ubiquitin ligases (STUbLs) and proteasomal degradation (19). Mammalian STUbLs include RNF4 and RNF111 (Arkadia) and viral STUbLs include varicella zoster virus ORF61, herpes simplex virus-1 ICP0, and KSHV K-Rta (19,20).…”

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confidence: 99%

“…Recent studies have demonstrated that poly-SUMO2/3 chains serve as a ubiquitination signal for SUMO-targeted ubiquitin ligases (STUbLs) and proteasomal degradation (19). Mammalian STUbLs include RNF4 and RNF111 (Arkadia) and viral STUbLs include varicella zoster virus ORF61, herpes simplex virus-1 ICP0, and KSHV K-Rta (19,20).…”

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confidence: 99%

The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1γ sumoylation and poly-SUMO chain elongation

Sohn

Hearing

2016

Proc. Natl. Acad. Sci. U.S.A.

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The adenovirus (Ad) early region 4 (E4)-ORF3 protein regulates diverse cellular processes to optimize the host environment for the establishment of Ad replication. E4-ORF3 self-assembles into multimers to form a nuclear scaffold in infected cells and creates distinct binding interfaces for different cellular target proteins. Previous studies have shown that the Ad5 E4-ORF3 protein induces sumoylation of multiple cellular proteins and subsequent proteasomal degradation of some of them, but the detailed mechanism of E4-ORF3 function remained unknown. Here, we investigate the role of E4-ORF3 in the sumoylation process by using transcription intermediary factor (TIF)-1γ as a substrate. Remarkably, we discovered that purified E4-ORF3 protein stimulates TIF-1γ sumoylation in vitro, demonstrating that E4-ORF3 acts as a small ubiquitin-like modifier (SUMO) E3 ligase. Furthermore, E4-ORF3 significantly increases poly-SUMO3 chain formation in vitro in the absence of substrate, showing that E4-ORF3 has SUMO E4 elongase activity. An E4-ORF3 mutant, which is defective in protein multimerization, exhibited severely decreased activity, demonstrating that E4-ORF3 self-assembly is required for these activities. Using a SUMO3 mutant, K11R, we found that E4-ORF3 facilitates the initial acceptor SUMO3 conjugation to TIF-1γ as well as poly-SUMO chain elongation. The E4-ORF3 protein displays no SUMO-targeted ubiquitin ligase activity in our assay system. These studies reveal the mechanism by which E4-ORF3 targets specific cellular proteins for sumoylation and proteasomal degradation and provide significant insight into how a small viral protein can play a role as a SUMO E3 ligase and E4-like SUMO elongase to impact a variety of cellular responses.A denoviruses (Ads) are ubiquitous pathogens that infect a wide range of vertebrates. Ad infection is generally associated with mild disease, but Ads have been increasingly recognized as significant pathogens in infants, the elderly, and immunocompromised patients (1). Ads have evolved diverse mechanisms to counteract host antiviral responses during infection (2). Successful Ad replication relies on functions provided by early region 4 (E4). The highly conserved E4-ORF3 protein assembles into a multimeric nuclear network, referred to as tracks (3), in infected cells (4, 5). The Ad5 E4-ORF3 protein recruits numerous cellular proteins into nuclear tracks including promylocytic leukemia (PML) nuclear body components (3), the Mre11-Rad50-Nbs1 (MRN) complex (6, 7), small ubiquitin-like modifier (SUMO) proteins (8), transcription intermediary factor (TIF)-1α (9), TIF-1γ (10), and TFII-I (11). This event causes sequestration of the target proteins inhibiting their antiviral functions. Relocalization of TIF-1γ and TFII-I by Ad5 E4-ORF3 results in their proteasomal degradation (12, 13). We previously showed that Ad5 E4-ORF3 mediates sumoylation of multiple cellular proteins (8,11,13) and suggested that E4-ORF3-induced sumoylation triggers ubiquitination and proteasomal degradation of some substrates....

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“…In many cases, ubiquitylation by RNF4 leads to proteasomal degradation; for example, SUMO-dependent ubiquitylation by RNF4 leads to degradation of the promyelocytic leukemia (PML) protein and its related oncogenic fusion protein PML-RAR (a fusion between PML and the retinoic acid receptor a). Moreover, expression of RNF4 results in differentiation of PML-RAR leukemic cells, 6 suggesting that RNF4 functions as a tumor suppressor in promyelocytic leukemia. In contrast, in the case of epithelial cancers RNF4-dependent ubiquitylation potentiates the tumorigenic properties of cancer cells.…”

Section: Dysregulated Proteostasis In Cancermentioning

confidence: 99%

“…RNF4 stabilizing activity also requires its association with nucleosomes. A point mutation, K179D, that blocks this association prevents ubiquitylation, stabilization, and transcriptional enhancement, 5,6 suggesting that RNF4 acts on, or in the vicinity of, chromatin. Nevertheless, how atypical ubiquitylation and association with nucleosomes results in oncoprotein potentiation is not clear.…”

Section: Mechanisms Of Rnf4-dependent Stabilization and Oncogene Actimentioning

confidence: 99%

Stabilization of nuclear oncoproteins by RNF4 and the ubiquitin system in cancer

Diefenbacher

Orian

2016

Molecular & Cellular Oncology

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RNF4, a SUMO-targeted ubiquitin ligase, stabilizes a selected group of oncoproteins. It potentiates oncoprotein activity and serves as a positive feedback agonist of Wnt and Notch pathways. RNF4 is essential for cancer cell survival and its levels are elevated in human cancers, correlating with poor outcome in a subset of cancer patients. KEYWORDSGene-regulation; oncogene; phosphorylation; RNF4; ubiquitin Dysregulated proteostasis in cancerCancer is intimately linked to dysregulated proteolysis. Twenty-five years ago, Ciechanover et al. observed that nuclear oncoproteins are short-lived and degraded by the ubiquitin system. 1 Over the next 2 1 / 2 decades it became apparent that degradation of oncoproteins requires phosphorylation by mitogenic kinases. Mutations of these phosphorylation sites (e.g., Myc T58A , b-Catenin S33A ) are identified frequently in cancer patients and are sufficient to impair degradation and promote tumorigenesis in mouse models. In addition, enzymes and scaffold proteins that mediate the degradation of these phosphooncoproteins are often mutated or inactivated in human cancers (e.g., the tumor-suppressors F-box/WD repeat-containing protein 7 [FBXW7] and adenomatous polyposis coli [APC]). Collectively, deregulated stabilization and increased abundance of oncoproteins are at the heart of tumorigenesis. [2][3][4] In many cases, destabilized phosphorylation is preceded by a priming phosphorylation event that initially potentiates the activity of oncogenes by poorly understood mechanisms. These phosphorylations are essential for the subsequent recruitment of kinases that catalyze secondary destabilizing phosphorylations. For example, phosphorylation of c-Myc S62 by mitogenactivated protein kinases (MAPKs) primes for glycogen synthase kinase-3b (GSK3b) phosphorylation of T58 of c-Myc and subsequent ubiquitylation-dependent degradation by the FbW7 ligase complex. 3 Likewise, phosphorylation of b-catenin S45 by casein-kinase-I .CKI/ is required for phosphorylation by GSK3b and ubiquitylation by the SCF bTRCP ubiquitin ligase complex. 4 However, the mechanism(s) by which these initial phosphorylations enhance the stability and activity of oncogenic transcription factors, as well as their contribution to cancer, is less clear.In a recent study, 5 we identified that RNF4, a ubiquitin ligase, and the ubiquitin system is part of the machinery involved in stabilization, rather than degradation, of selected short-lived oncoproteins such as b-Catenin, c-Myc, c-Jun, and Notch intracellular domain protein (N-ICD): RNF4 potentiates the transcriptional activity of these oncoproteins, enhances the tumorigenic properties of cancer cells, and is essential for cancer cell survival. Importantly, high RNF4 levels correlate with poor outcome in a subset of cancers. 5 RNF4 belongs to a small group of RING (really interesting new gene) ubiquitin ligases termed SUMO-Targeted Ubiquitin ligases (STUbL). Conserved from yeast to man, these ligases bind to SUMO chains of SUMOylated proteins via multiple SIM domain...

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SUMO-targeted ubiquitin ligases

Cited by 215 publications

References 163 publications

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

RNF 4 interacts with both SUMO and nucleosomes to promote the DNA damage response

The adenovirus E4-ORF3 protein functions as a SUMO E3 ligase for TIF-1γ sumoylation and poly-SUMO chain elongation

Stabilization of nuclear oncoproteins by RNF4 and the ubiquitin system in cancer

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