RanBP2/Nup358 enhances miRNA activity by sumoylating and stabilizing Argonaute 1

Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of the interleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 messenger ribonucleoprotein (mRNP) recruits Argonautes bound to let-7 microRNA. After this mRNP is exported to the cytosol, RanBP2 sumoylates mRNP-associated Argonautes, thereby stabilizing them and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.

Download Full-text

Acute Necrotizing Encephalopathy: An Underrecognized Clinicoradiologic Disorder

Mediators of Inflammation ◽

10.1155/2015/792578 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 31

Author(s):

Xiujuan Wu ◽

Wei Wu ◽

Wei Pan ◽

Limin Wu ◽

Kangding Liu ◽

...

Keyword(s):

Viral Infections ◽

Febrile Illness ◽

Nuclear Pore ◽

Missense Mutations ◽

Gene Encoding ◽

Acute Necrotizing Encephalopathy ◽

Nuclear Pore Protein ◽

Distinctive Type ◽

Acute Necrotizing ◽

Magnetic Resonance Imaging Mri

Acute necrotizing encephalopathy (ANE) is a rare but distinctive type of acute encephalopathy with global distribution. Occurrence of ANE is usually preceded by a virus-associated febrile illness and ensued by rapid deterioration. However, the causal relationship between viral infections and ANE and the exact pathogenesis of ANE remain unclear; both environmental and host factors might be involved. Most cases of ANE are sporadic and nonrecurrent, namely, isolated or sporadic ANE; however, few cases are recurrent and with familial episodes. The recurrent and familial forms of ANE were found to be incompletely autosomal-dominant. Further the missense mutations in the gene encoding the nuclear pore protein Ran Binding Protein 2 (RANBP2) were identified. Although the clinical course and the prognosis of ANE are diverse, the hallmark of neuroradiologic manifestation of ANE is multifocal symmetric brain lesions which are demonstrated by computed tomography (CT) or magnetic resonance imaging (MRI). The treatment of ANE is still under investigation. We summarize the up-to-date knowledge on ANE, with emphasis on prompt diagnosis and better treatment of this rare but fatal disease.

Download Full-text

COVID-19 Associated Acute Necrotizing Encephalopathy in a Hospitalized Cohort in Oregon

10.21203/rs.3.rs-92356/v1 ◽

2020 ◽

Author(s):

Holly Vanni ◽

Austin D Jou ◽

Christine E Choo ◽

Eric C. Walter ◽

Richard A. Mularksi

Keyword(s):

Observational Studies ◽

Viral Infections ◽

Case Reports ◽

Health Maintenance Organization ◽

Time Frame ◽

Health Maintenance ◽

Acute Necrotizing Encephalopathy ◽

Acute Necrotizing ◽

The Central Nervous System ◽

Novel Coronavirus

Abstract Background/Objective: Severe Acute Respiratory Syndrome Coronavirus-2 (SARSCoV-2) is a novel coronavirus strain that most commonly affects the respiratory system with observational studies and case reports suggesting this virus may target the central nervous system. To date there has been one case report of COVID-19 related acute necrotizing encephalopathy.Methods: Observational study of COVID-19 patients admitted to two hospitals of a large metropolitan health maintenance organization serving over 600,000 members using retrospective electronic and radiographic medical record evaluation across 4 months (March – June of 2020) after multiple cases of acute necrotizing encephalopathy were diagnosed.Results: During this time frame 216 patients were diagnosed with COVID-19, 106 (49%) required hospitalization, 21 (20%) required admission to the intensive care unit (ICU) and 18 (17%) required intubation. Of the 18, 4 (22%) had clinicoradiologic evidence of acute necrotizing encephalopathy (ANE) diagnosed, two with associated areas of hemorrhage.Conclusions: Acute necrotizing encephalopathy (ANE) with or without hemorrhage, is a rare CNS disease, usually seen in childhood as a complication of viral infections. We identified a high percentage of COVID-19 patients with clinicoradiologic evidence of acute necrotizing encephalopathy in our cohort. To our knowledge, ANE has not been reported in patients with SARS or MERS. Understanding the pathogenesis, neurotropism and effects of the SARS-CoV-2 virus is important in developing treatments and improving morbidity and mortality.

Download Full-text

P249 Recurrent episodes of acute necrotizing encephalopathy caused by a mutation in a component of the nuclear pore, RANBP2

European Journal of Paediatric Neurology ◽

10.1016/s1090-3798(09)70307-1 ◽

2009 ◽

Vol 13 ◽

pp. S98-S99

Author(s):

S. Mastroyianni ◽

A. Skardoutsou ◽

K. Voudris ◽

E. Katsarou ◽

J. Nikas ◽

...

Keyword(s):

Nuclear Pore ◽

Acute Necrotizing Encephalopathy ◽

Acute Necrotizing

Download Full-text

Acute Necrotizing Encephalopathy in an Adult

Journal of Clinical Imaging Science ◽

10.4103/2156-7514.156117 ◽

2015 ◽

Vol 5 ◽

pp. 20 ◽

Cited By ~ 4

Author(s):

Ramakrishna Narra ◽

Adinarayana Mandapalli ◽

Suseel Kumar Kamaraju

Keyword(s):

Poor Prognosis ◽

Viral Infections ◽

Mortality Rates ◽

Magnetic Resonance Imaging Examination ◽

High Morbidity ◽

Resonance Imaging ◽

Neurologic Disorder ◽

Acute Necrotizing Encephalopathy ◽

Healthy Infants ◽

Acute Necrotizing

Acute necrotizing encephalopathy (ANE) is a rapidly progressing neurologic disorder that occurs in children after common viral infections of the respiratory or gastrointestinal systems. This disease is commonly seen in East Asia. Normal healthy infants and children can get affected. The condition carries a poor prognosis with high morbidity and mortality rates. We report here a case of a 23-year-old female with ANE and describe its neuroimaging findings. Magnetic resonance imaging examination performed showed symmetric lesions involving the thalami, brainstem, and cerebellum.

Download Full-text

COVID-19 Associated Acute Necrotizing Encephalopathy in a Hospitalized Cohort in Oregon

10.21203/rs.3.rs-92356/v2 ◽

2020 ◽

Author(s):

Holly Vanni ◽

Austin D Jou ◽

Christine E Choo ◽

Eric C. Walter ◽

Richard A. Mularksi

Keyword(s):

Observational Studies ◽

Viral Infections ◽

Case Reports ◽

Health Maintenance Organization ◽

Time Frame ◽

Health Maintenance ◽

Acute Necrotizing Encephalopathy ◽

Acute Necrotizing ◽

The Central Nervous System ◽

Novel Coronavirus

Abstract Background/Objective: Severe Acute Respiratory Syndrome Coronavirus-2 (SARSCoV-2) is a novel coronavirus strain that most commonly affects the respiratory system with observational studies and case reports suggesting this virus may target the central nervous system. To date there has been one case report of COVID-19 related acute necrotizing encephalopathy.Methods: Observational study of COVID-19 patients admitted to two hospitals of a large metropolitan health maintenance organization serving over 600,000 members using retrospective electronic and radiographic medical record evaluation across 4 months (March – June of 2020) after multiple cases of acute necrotizing encephalopathy were diagnosed.Results: During this time frame 216 patients were diagnosed with COVID-19, 106 (49%) required hospitalization, 21 (20%) required admission to the intensive care unit (ICU) and 18 (17%) required intubation. Of the 18, 4 (22%) had clinicoradiologic evidence of acute necrotizing encephalopathy (ANE) diagnosed, two with associated areas of hemorrhage.Conclusions: Acute necrotizing encephalopathy (ANE) with or without hemorrhage, is a rare CNS disease, usually seen in childhood as a complication of viral infections. We identified a high percentage of COVID-19 patients with clinicoradiologic evidence of acute necrotizing encephalopathy in our cohort. To our knowledge, ANE has not been reported in patients with SARS or MERS. Understanding the pathogenesis, neurotropism and effects of the SARS-CoV-2 virus is important in developing treatments and improving morbidity and mortality.

Download Full-text

Infection-Triggered Familial or Recurrent Cases of Acute Necrotizing Encephalopathy Caused by Mutations in a Component of the Nuclear Pore, RANBP2

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2008.12.009 ◽

2009 ◽

Vol 84 (1) ◽

pp. 44-51 ◽

Cited By ~ 161

Author(s):

Derek E. Neilson ◽

Mark D. Adams ◽

Caitlin M.D. Orr ◽

Deborah K. Schelling ◽

Robert M. Eiben ◽

...

Keyword(s):

Nuclear Pore ◽

Acute Necrotizing Encephalopathy ◽

Acute Necrotizing

Download Full-text

Structure, assembly and interactions of the nuclear lamina and the nuclear pore complex

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010012285x ◽

1992 ◽

Vol 50 (1) ◽

pp. 490-491

Author(s):

N. Panté ◽

M. Jarnik ◽

E. Heitlinger ◽

U. Aebi

Keyword(s):

Nuclear Pore Complex ◽

Divalent Cations ◽

Nuclear Lamina ◽

Dynamic Structure ◽

Nucleocytoplasmic Transport ◽

Nuclear Pore ◽

Cytoplasmic Filaments ◽

Radial Spokes ◽

Nuclear Ring ◽

Central Plug

The nuclear pore complex (NPC) is a ∼120 MD supramolecular machine implicated in nucleocytoplasmic transport, that is embedded in the double-membraned nuclear envelope (NE). The basic framework of the ∼120 nm diameter NPC consists of a 32 MD cytoplasmic ring, a 66 MD ‘plug-spoke’ assembly, and a 21 MD nuclear ring. The ‘central plug’ seen in en face views of the NPC reveals a rather variable appearance indicating that it is a dynamic structure. Projecting from the cytoplasmic ring are 8 short, twisted filaments (Fig. 1a), whereas the nuclear ring is topped with a ‘fishtrap’ made of 8 thin filaments that join distally to form a fragile, 30-50 nm distal diameter ring centered above the NPC proper (Fig. 1b). While the cytoplasmic filaments are sensitive to proteases, they as well as the nuclear fishtraps are resistant to RNase treatment. Removal of divalent cations destabilizes the distal rings and thereby opens the fishtraps, addition causes them to reform. Protruding from the tips of the radial spokes into perinuclear space are ‘knobs’ that might represent the large lumenal domain of gp210, a membrane-spanning glycoprotein (Fig. 1c) which, in turn, may play a topogenic role in membrane folding and/or act as a membrane-anchoring site for the NPC. The lectin wheat germ agglutinin (WGA) which is known to recognize the ‘nucleoporins’, a family of glycoproteins having O-linked N-acetyl-glucosamine, is found in two locations on the NPC (Fig. 1. d-f): (i) whereas the cytoplasmic filaments appear unlabelled (Fig. 1d&e), WGA-gold labels sites between the central plug and the cytoplasmic ring (Fig. le; i.e., at a radius of 25-35 nm), and (ii) it decorates the distal ring of the nuclear fishtraps (Fig. 1, d&f; arrowheads).

Download Full-text