Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin.

Haas, Arthur; Ahrens, Patricia Buckley; Bright, P M; Ankel, Helmut

doi:10.1016/s0021-9258(18)60961-5

Cited by 412 publications

(93 citation statements)

References 40 publications

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“…Our model is that RNF213 might recognize multi-ISGylated proteins as the entry point of a novel pathway for further processing of multi-ISGylated proteins at lipid droplets. While RNF4 & poly-SUMOylation are both induced by nuclear stress, RNF213 and multi-ISGylation are induced by IFN-I signaling 60,65 . Moreover, co-regulation of ISG15 and RNF213 was previously observed in a large-scale analysis of protein quantitative trait loci (pQTL) 66 , also suggesting that both proteins operate in the same cellular pathway.…”

Section: Discussionmentioning

confidence: 99%

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Thery

Martina

Asselman

et al. 2021

Preprint

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ISG15 is an interferon-stimulated, ubiquitin-like protein that can conjugate to substrate proteins (ISGylation) to counteract microbial infection, but the underlying mechanisms remain elusive. Here, we used a viral-like particle trapping technology to identify ISG15-binding proteins and discovered Ring Finger Protein 213 (RNF213) as an ISG15 interactor and cellular sensor of ISGylated proteins. RNF213 is a poorly-characterized, interferon-induced megaprotein that is frequently mutated in Moyamoya disease, a rare cerebrovascular disorder. We found that interferon induces ISGylation and oligomerization of RNF213 on lipid droplets, where it acts as a sensor for ISGylated proteins. We showed that RNF213 has broad antimicrobial activity in vitro and in vivo, counteracting infection with Listeria monocytogenes, herpes simplex virus 1 (HSV-1), human respiratory syncytial virus (RSV) and coxsackievirus B3 (CVB3), and we observed a striking co-localization of RNF213 with intracellular bacteria. Together, our findings provide novel molecular insights into the ISGylation pathway and reveal RNF213 as a key antimicrobial effector.

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Section: Discussionmentioning

confidence: 99%

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Thery

Martina

Asselman

et al. 2021

Preprint

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“…The RELATED TO UBIQUITIN (RUB, also known as NEDD8 in mammals and yeast) is a Ub like protein (Haas et al ., 1987; Rao‐Naik et al ., 1998). Like the ubiquitylation process, RUB modification, called RUBylation, is also accomplished by E1, E2 and E3 enzymes.…”

Section: Introductionmentioning

confidence: 99%

Small kernel 501 (smk501) encodes the RUBylation activating enzyme E1 subunit ECR1 (E1 C‐TERMINAL RELATED 1) and is essential for multiple aspects of cellular events during kernel development in maize

et al. 2021

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Summary RUBylation plays essential roles in plant growth and development through regulating Cullin‐RING ubiquitin E3 ligase (CRL) activities and the CRL‐mediated protein degradations. However, the function of RUBylation in regulating kernel development remains unclear. Through genetic and molecular analyses of a small kernel 501 (smk501) mutant in maize (Zea mays), we cloned the smk501 gene, revealed its molecular function, and defined its roles in RUBylation pathway and seed development. Smk501 encodes a RUBylation activating enzyme E1 subunit ZmECR1 (E1 C‐TERMINAL RELATED 1) protein. Destruction in RUBylation by smk501 mutation resulted in less embryo and endosperm cell number and smaller kernel size. The transcriptome and proteome profiling, hormone evaluation and cell proliferation observation revealed that disturbing ZmECR1 expression mainly affects pathways on hormone signal transduction, cell cycle progression and starch accumulation during kernel development. In addition, mutant in zmaxr1 (Auxin resistant 1), another RUB E1 subunit, also showed similar defects in kernel development. Double mutation of zmecr1 and zmaxr1 lead to empty pericarp kernel phenotype. RUBylation is a novel regulatory pathway affecting maize kernel development, majorly through its functions in modifying multiple cellular progresses.

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“…The binding of IFN-a/b to its receptor activates the Janus kinasesignal transducer and activator of transcription (JAK/STAT) pathway, inducing the transcription of stimulated genes (ISGs), including IFN-a/b (Platanias, 2005). One of the most important ISGs expressed is ISG15, which is a 15 kDa ubiquitin-like protein with two ubiquitin-like domains, and is processed from a 17 kDa precursor (Blomstrom et al, 1986;Farrell et al, 1979;Haas et al, 1987). It has been implicated in exerting a direct or indirect antiviral effect (reviewed by Harty et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling

Bakshi

Holzer

Bridgen³

et al. 2013

Journal of General Virology

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The ovarian tumour (OTU) domain of the nairovirus L protein has been shown to remove ubiquitin and interferon-stimulated gene 15 protein (ISG15) from host cell proteins, which is expected to have multiple effects on cell signalling pathways. We have confirmed that the OTU domain from the L protein of the apathogenic nairovirus Dugbe virus has deubiquitinating and deISGylating activity and shown that, when expressed in cells, it is highly effective at blocking the TNF-α/NF-κB and interferon/JAK/STAT signalling pathways even at low doses. Point mutations of the catalytic site of the OTU [C40A, H151A and a double mutant] both abolished the ability of the OTU domain to deubiquitinate and deISGylate proteins and greatly reduced its effect on cell signalling pathways, confirming that it is this enzymic activity that is responsible for blocking the two signalling pathways. Expression of the inactive mutants at high levels could still block signalling, suggesting that the viral OTU can still bind to its substrate even when mutated at its catalytic site. The nairovirus L protein is a very large protein that is normally confined to the cytoplasm, where the virus replicates. When the OTU domain was prevented from entering the nucleus by expressing it as part of the N-terminal 205 kDa of the viral L protein, it continued to block type I interferon signalling, but no longer blocked the TNF-α-induced activation of NF-κB.

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Interferon induces a 15-kilodalton protein exhibiting marked homology to ubiquitin.

Cited by 412 publications

References 40 publications

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Ring Finger Protein 213 Assembles into a Sensor for ISGylated Proteins with Antimicrobial Activity

Small kernel 501 (smk501) encodes the RUBylation activating enzyme E1 subunit ECR1 (E1 C‐TERMINAL RELATED 1) and is essential for multiple aspects of cellular events during kernel development in maize

Dugbe virus ovarian tumour domain interferes with ubiquitin/ISG15-regulated innate immune cell signalling

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