The RING finger protein family in health and disease

Cai, Chunmei; Tang, Yan-Dong; Zhai, Jingbo; Zheng, Chunfu

doi:10.1038/s41392-022-01152-2

Cited by 62 publications

(49 citation statements)

References 328 publications

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“…No binding was observed to RNF128 which is a related transmembrane E3 ligase of the same subfamily ( Figure 6B, C , red sensogram) and no binding was observed to RNF167 testing an unrelated receptor ECD ( Figure 6—figure supplement 1A ). RNF167 is a member of the transmembrane PA-TM-RING E3 ligase family with approximately 10 members and exert widespread involvement in several diseases ( Cai et al, 2022 ). These E3 ligases are minimally defined by three conserved domains, a protease-associated (PA) domain that acts as a substrate recruitment domain, a transmembrane domain (TM), and a RING-H2 finger (RNF) ( Nakamura, 2011 ).…”

Section: Resultsmentioning

confidence: 99%

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Siepe

Henneberg

Wilson

et al. 2022

eLife

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Secreted proteins, which include cytokines, hormones and growth factors, are extracellular ligands that control key signaling pathways mediating cell-cell communication within and between tissues and organs. Many drugs target secreted ligands and their cell-surface receptors. Still, there are hundreds of secreted human proteins that either have no identified receptors ('orphans') and are likely to act through cell surface receptors that have not yet been characterized. Discovery of secreted ligand-receptor interactions by high-throughput screening has been problematic, because the most commonly used high-throughput methods for protein-protein interaction (PPI) screening do not work well for extracellular interactions. Cell-based screening is a promising technology for definition of new ligand-receptor interactions, because multimerized ligands can enrich for cells expressing low affinity cell-surface receptors, and such methods do not require purification of receptor extracellular domains. Here, we present a proteo-genomic cell-based CRISPR activation (CRISPRa) enrichment screening platform employing customized pooled cell surface receptor sgRNA libraries in combination with a magnetic bead selection-based enrichment workflow for rapid, parallel ligand-receptor deorphanization. We curated 80 potentially high value orphan secreted proteins and ultimately screened 20 secreted ligands against two cell sgRNA libraries with targeted expression of all single-pass (TM1) or multi-pass (TM2+) receptors by CRISPRa. We identified previously unknown interactions in 12 of these screens, and validated several of them using surface plasmon resonance and/or cell binding. The newly deorphanized ligands include three receptor tyrosine phosphatase (RPTP) ligands and a chemokine like protein that binds to killer cell inhibitory receptors (KIR's). These new interactions provide a resource for future investigations of interactions between the human secreted and membrane proteomes.

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Section: Resultsmentioning

confidence: 99%

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Siepe

Henneberg

Wilson

et al. 2022

eLife

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Section: Pa-tm-ring E3 Ligase Nanobodies For Receptor Eliminationmentioning

confidence: 99%

Section: Mainmentioning

confidence: 99%

“…The human transmembrane (TM) E3 ligase family represents a class of diverse RING type E3 ubiquitin ligases (Cai et al, 2022; Deshaies and Joazeiro, 2009) with approximately 50 members (Fig.1A upper chart). These proteins exert widespread involvement in several diseases and cancer (Cai et al, 2022; Chen et al, 2022). The family can be further grouped into subcellular and structurally related sub classes, the plasma membrane localized E3 TM ligases include: RING domain containing proteins (7), PA-TM-RING (10), RING between RING (RBR; 5) and the membrane-associated RING-CH (MARCH; 4) families (Figure 1A, lower chart).…”

Section: Mainmentioning

confidence: 99%

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Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

Siepe

Picton

Garcia

2022

Preprint

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In recent years, targeted protein degradation (TPD) of plasma membrane proteins by hijacking the ubiquitin proteasome system (UPS) or the lysosomal pathway have emerged as novel therapeutic avenues in drug development to address and inhibit canonically difficult targets. While TPD strategies have been successful to target cell surface receptors, these approaches are limited by the availability of suitable binders to generate heterobifunctional molecules. Here, we present the development of a nanobody (VHH) based degradation toolbox termed REULR (Receptor Elimination by E3 Ubiquitin Ligase Recruitment). We generated human and mouse cross-reactive nanobodies against 5 transmembrane PA-TM-RING type E3 Ubiquitin Ligases (RNF218, RNF130, RNF167, RNF43, ZNRF3) covering a broad range and selectivity of tissue expression with which we characterized expression in human and mouse cell lines and immune cells (PBMCs). We demonstrate that heterobifunctional REULR molecules can enforce transmembrane E3 ligase interaction with a variety of disease relevant target receptors (EGFR, EPOR, PD-1) by induced proximity resulting in effective membrane clearance of the target receptor at varying levels. In addition, we designed E3 Ligase self-degrading molecules, "fratricide" REULRs (RNF128, RNF130, RENF167, RNF43, ZNRF3), that allow downregulation of one or several E3 Ligases from the cell surface and consequently modulate receptor signaling strength. REULR molecules represent a VHH-based, modular and versatile "mix and match" targeting strategy for facile modulation of cell surface proteins by induced proximity to transmembrane PA-TM-RING E3 ligases.

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“…NF-κB pathway also plays an important role in the control of immunity, inflammation and other processes ( 33 ). The binding of viral pathogen-associated molecular patterns (PAMPs) to their receptor host pathogen recognition receptors (PRRs) triggers natural immunity and activates IFN regulatory factor (IRF) family members as well as NF-κB and thus promotes the expression of downstream ISGs ( 34 ). The transcription factor NF-κB proteins consist of the Rel family of proteins which include RelA (P65), RelB, c-Rel, p105/p50 (NF-κB1) and p100/p52 (NF-κB2) ( 35 ).…”

Section: Introductionmentioning

confidence: 99%

HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway

et al. 2022

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Classical swine fever (CSF), caused by the classical swine fever virus (CSFV), is a highly contagious and fatal viral disease, posing a significant threat to the swine industry. Heat shock protein 90 kDa alpha class A member 1 (HSP90AA1) is a very conservative chaperone protein that plays an important role in signal transduction and viral proliferation. However, the role of HSP90AA1 in CSFV infection is unknown. In this study, we found that expression of HSP90AA1 could be promoted in PK-15 and 3D4/2 cells infected by CSFV. Over-expression of HSP90AA1 could inhibit CSFV replication and functional silencing of HSP90AA1 gene promotes CSFV replication. Further exploration revealed that HSP90AA1 interacted with CSFV NS5A protein and reduced the protein levels of NS5A. Since NS5A has an important role in CSFV replication and is closely related to type I IFN and NF-κB response, we further analyzed whether HSP90AA1 affects CSFV replication by regulating type I IFN and NF-κB pathway responses. Our research found HSP90AA1 positively regulated type I IFN response by promoting STAT1 phosphorylation and nuclear translocation processes and promoted the nuclear translocation processes of p-P65. However, CSFV infection antagonizes the activation of HSP90AA1 on JAK/STAT and NF-κB pathway. In conclusion, our study found that HSP90AA1 overexpression significantly inhibited CSFV replication and may inhibit CSFV replication by interacting with NS5A and activating JAK/STAT and NF-κB signaling pathways. These results provide new insights into the mechanism of action of HSP90AA1 in CSFV infection, which abundant the candidate library of anti-CSFV.

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The RING finger protein family in health and disease

Cited by 62 publications

References 328 publications

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Identification of orphan ligand-receptor relationships using a cell-based CRISPRa enrichment screening platform

Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox

HSP90AA1 interacts with CSFV NS5A protein and regulates CSFV replication via the JAK/STAT and NF-κB signaling pathway

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