scholarly journals Screen for multi-SUMO–binding proteins reveals a multi-SIM–binding mechanism for recruitment of the transcriptional regulator ZMYM2 to chromatin

2015 ◽  
Vol 112 (35) ◽  
pp. E4854-E4863 ◽  
Author(s):  
Elisa Aguilar-Martinez ◽  
Xi Chen ◽  
Aaron Webber ◽  
A. Paul Mould ◽  
Anne Seifert ◽  
...  
Keyword(s):  
Transcriptional Control ◽  
Ring Finger ◽  
Binding Activity ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Binding Partner ◽  
Finger Protein ◽  
Sumo Binding Proteins ◽  
Nuclear Processes ◽  
Regulatory Event

Protein SUMOylation has emerged as an important regulatory event, particularly in nuclear processes such as transcriptional control and DNA repair. In this context, small ubiquitin-like modifier (SUMO) often provides a binding platform for the recruitment of proteins via their SUMO-interacting motifs (SIMs). Recent discoveries point to an important role for multivalent SUMO binding through multiple SIMs in the binding partner as exemplified by poly-SUMOylation acting as a binding platform for ubiquitin E3 ligases such as ring finger protein 4. Here, we have investigated whether other types of protein are recruited through multivalent SUMO interactions. We have identified dozens of proteins that bind to multi-SUMO platforms, thereby uncovering a complex potential regulatory network. Multi-SUMO binding is mediated through multi-SIM modules, and the functional importance of these interactions is demonstrated for the transcriptional corepressor ZMYM2/ZNF198 where its multi-SUMO–binding activity is required for its recruitment to chromatin.

scholarly journals The RING Finger Protein SNURF Is a Bifunctional Protein Possessing DNA Binding Activity

2001 ◽  
Vol 276 (26) ◽  
pp. 23653-23660 ◽  
Author(s):  
Marika Häkli ◽  
Ulla Karvonen ◽  
Olli A. Jänne ◽  
Jorma J. Palvimo
Keyword(s):  
Dna Binding ◽  
Ring Finger ◽  
Binding Activity ◽  
Ring Finger Protein ◽  
Bifunctional Protein ◽  
Dna Binding Activity ◽  
Finger Protein

scholarly journals RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling

2017 ◽  
Vol 313 (5) ◽  
pp. C584-C592 ◽  
Author(s):  
Travis Lear ◽  
Sarah R. Dunn ◽  
Alison C. McKelvey ◽  
Aazrin Mir ◽  
John Evankovich ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Ring Finger ◽  
Vital Role ◽  
Receptor Type ◽  
Mechanistic Study ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Cxcr4 Signaling ◽  
Finger Protein

As an α-chemokine receptor specific for stromal-derived-factor-1 (SDF-1, also called CXCL12), C-X-C chemokine receptor type 4 (CXCR4) plays a vital role in chemotactically attracting lymphocytes during inflammation. CXCR4 also regulates HIV infection due to its role as one of the chemokine coreceptors for HIV entry into CD4+ T cells. Chemokine receptors and their signaling pathways have been shown to be regulated by the process of ubiquitination, a posttranslational modification, guided by ubiquitin E3 ligases, which covalently links ubiquitin chains to lysine residues within target substrates. Here we describe a novel mechanism regulating CXCR4 protein levels and subsequent CXCR4/CXCL12 signaling pathway through the ubiquitination and degradation of the receptor in response to ligand stimulation. We identify that an uncharacterized really interesting new gene (RING) finger ubiquitin E3 ligase, RING finger protein 113A (RNF113A), directly ubiquitinates CXCR4 in cells, leading to CXCR4 degradation, and therefore disrupts the signaling cascade. We determined that the K331 residue within CXCR4 is essential for RNF113A-mediated ubiquitin conjugation. Overexpression of RNF113A significantly reduces CXCL12-induced kinase activation in HeLa cells, whereas RNF113A knockdown enhances CXCL12-induced downstream signaling. Further, RNF113A expression and silencing directly affect cell motility in a wound healing assay. These results suggest that RNF113A plays an important role in CXCR4 signaling through the ubiquitination and degradation of CXCR4. This mechanistic study might provide new understanding of HIV immunity and neutrophil activation and motility regulated by CXCR4.

scholarly journals Critical Role of the Ubiquitin Ligase Activity of UHRF1, a Nuclear RING Finger Protein, in Tumor Cell Growth

2005 ◽  
Vol 16 (12) ◽  
pp. 5621-5629 ◽  
Author(s):  
Yonchu Jenkins ◽  
Vadim Markovtsov ◽  
Wayne Lang ◽  
Poonam Sharma ◽  
Denise Pearsall ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Tumor Cell ◽  
A549 Cells ◽  
Ring Finger ◽  
Cell Cycle Checkpoints ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Finger Protein ◽  
Nuclear Ring

Early cellular events associated with tumorigenesis often include loss of cell cycle checkpoints or alteration in growth signaling pathways. Identification of novel genes involved in cellular proliferation may lead to new classes of cancer therapeutics. By screening a tetracycline-inducible cDNA library in A549 cells for genes that interfere with proliferation, we have identified a fragment of UHRF1 (ubiquitin-like protein containing PHD and RING domains 1), a nuclear RING finger protein, that acts as a dominant negative effector of cell growth. Reduction of UHRF1 levels using an UHRF1-specific shRNA decreased growth rates in several tumor cell lines. In addition, treatment of A549 cells with agents that activated different cell cycle checkpoints resulted in down-regulation of UHRF1. The primary sequence of UHRF1 contains a PHD and a RING motif, both of which are structural hallmarks of ubiquitin E3 ligases. We have confirmed using an in vitro autoubiquitination assay that UHRF1 displays RING-dependent E3 ligase activity. Overexpression of a GFP-fused UHRF1 RING mutant that lacks ligase activity sensitizes cells to treatment with various chemotherapeutics. Taken together, our results suggest a general requirement for UHRF1 in tumor cell proliferation and implicate the RING domain of UHRF1 as a functional determinant of growth regulation.

scholarly journals Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia

2015 ◽  
Vol 112 (24) ◽  
pp. 7548-7550 ◽  
Author(s):  
Bon-Kyoung Koo ◽  
Johan H. van Es ◽  
Maaike van den Born ◽  
Hans Clevers
Keyword(s):  
Target Genes ◽  
Ring Finger ◽  
Paneth Cells ◽  
Tumor Formation ◽  
Therapeutic Window ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Intestinal Neoplasia ◽  
Finger Protein ◽  
G Protein Coupled

Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend on, secreted Wnts. We previously showed that mutation of RZ in the intestine yields rapidly growing adenomas containing LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) stem cells and Wnt3-producing Paneth cells. We now show that removal of Paneth cells by Math1 mutation inhibits RZ−/− tumor formation. Similarly, deletion of Wnt3 inhibits tumorigenesis. Treatment of mice carrying RZ−/− intestinal neoplasia with a small molecule Wnt secretion inhibitor (porcupine inhibitor C59) strongly inhibited growth, whereas adjacent normal crypts remained intact. These results establish that paracrine Wnt secretion is an essential driver of RZ−/− tumor growth and imply that a therapeutic window exists for the use of porcupine inhibitors for RZ-mutant cancers.

scholarly journals Porcine RING Finger Protein 114 Inhibits Classical Swine Fever Virus Replication via K27-Linked Polyubiquitination of Viral NS4B

2019 ◽  
Vol 93 (21) ◽  
Author(s):  
Yuexiu Zhang ◽  
Huawei Zhang ◽  
Guang-Lai Zheng ◽  
Qian Yang ◽  
Shaoxiong Yu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Classical Swine Fever ◽  
Ring Domain ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Finger Protein ◽  
Ubiquitin Ligase Activity ◽  
Ns4b Protein

ABSTRACT In the host, many RING domain E3 ligases have been reported to inhibit viral replication through various mechanisms. In a previous screen, we found that porcine RING finger protein 114 (pRNF114), a RING domain E3 ubiquitin ligase, inhibits classical swine fever virus (CSFV) replication. This study aimed to clarify the underlying antiviral mechanism of pRNF114 against CSFV. Upon CSFV infection, pRNF114 mRNA was upregulated both in vitro and in vivo. CSFV replication was significantly suppressed in PK-pRNF114 cells stably expressing pRNF114 by the lentivirus-delivered system, whereas CSFV growth was enhanced in PK-15 cells with RNF114 knockout by the CRISPR/Cas9 system. The RING domain of pRNF114, which has E3 ubiquitin ligase activity, is crucial for its antiviral activity. Mechanistically, pRNF114 interacted with the CSFV NS4B protein through their C-terminal domains, which led to the K27-linked polyubiquitination and degradation of NS4B through a proteasome-dependent pathway. Collectively, these findings indicate that pRNF114 as a critical regulator of CSFV replication and uncover a mechanism by which pRNF114 employs its E3 ubiquitin ligase activity to inhibit CSFV replication. IMPORTANCE Porcine RING finger protein 114 (pRNF114) is a member of the RING domain E3 ligases. In this study, it was shown that pRNF114 is a potential anti-CSFV factor and the anti-CSFV effect of pRNF114 depends on its E3 ligase activity. Notably, pRNF114 targets and catalyzes the K27-linked polyubiquitination of the NS4B protein and then promotes proteasome-dependent degradation of NS4B, inhibiting the replication of CSFV. To our knowledge, pRNF114 is the first E3 ligase to be identified as being involved in anti-CSFV activity, and targeting NS4B could be a crucial route for antiviral development.

scholarly journals The functional analysis of Cullin 7 E3 ubiquitin ligases in cancer

Oncogenesis ◽  
2020 ◽  
Vol 9 (10) ◽  
Author(s):  
Le Shi ◽  
Dongyue Du ◽  
Yunhua Peng ◽  
Jiankang Liu ◽  
Jiangang Long
Keyword(s):  
Ring Finger ◽  
Tumor Promotion ◽  
Dependent Manner ◽  
Ring Finger Protein ◽  
E3 Ligases ◽  
Finger Protein ◽  
Novel Complex ◽  
Cullin 7 ◽  
Potential Use

Abstract Cullin (CUL) proteins have critical roles in development and cancer, however few studies on CUL7 have been reported due to its characteristic molecular structure. CUL7 forms a complex with the ROC1 ring finger protein, and only two F-box proteins Fbxw8 and Fbxw11 have been shown to bind to CUL7. Interestingly, CUL7 can interact with its substrates by forming a novel complex that is independent of these two F-box proteins. The biological implications of CUL-ring ligase 7 (CRL7) suggest that the CRL7 may not only perform a proteolytic function but may also play a non-proteolytic role. Among the existing studied CRL7-based E3 ligases, CUL7 exerts both tumor promotion and suppression in a context-dependent manner. Currently, the mechanism of CUL7 in cancer remains unclear, and no studies have addressed potential therapies targeting CUL7. Consistent with the roles of the various CRL7 adaptors exhibit, targeting CRL7 might be an effective strategy for cancer prevention and treatment. We systematically describe the recent major advances in understanding the role of the CUL7 E3 ligase in cancer and further summarize its potential use in clinical therapy.

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