Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection

Abstract

Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality. Despite this, it remains unclear howRanBP2 and its ANE1-associated mutations contribute to pathology. Mounting evidence has shown that RanBP2 interacts with distinct viruses to regulate viral infection. In addition, RanBP2 may regulate innate immune response pathways. This review summarizes recent advances in our understanding of how mutations in RANBP2 contribute to ANE1 and discusses how RanBP2 interacts with distinct viruses and affects viral infection. Recent findings indicate that RanBP2 might be an important therapeutic target, not only in the suppression of ANE1-driven cytokine storms, but also to combat hyperinflammation in response to viral infections.

Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy

“…In the case of mutations in RANBP2 , they are only 40% penetrant, at least according to the initial reports, and thus these alterations are often passed down by unaffected carriers. How these mutations cause ANE remains unclear [for excellent recent reviews on this topic see 2 , and 3 ]. This gene encodes the RanBP2/Nup358 protein, which is ubiquitously expressed and is part of the cytoplasmic filaments that are present on the cytoplasmic face of the nuclear pore complex [ 4 , 5 ] ( Figure 1a ).…”

Letter to the Editor in response to Dr. Josef Finsterer et al. “Intense work-up is required for pediatric COVID-related acute necrotizing encephalopathy with RANBP2 variants”

“…Concerning the terminology ANE and AHNE, they are two entities of the same spectrum of disorder, often with blurred boundaries not fully defined in the literature. The genetically determined recurrent form of this spectrum of disease is referred as ANE1 [ 2 ]. A recent manuscript published after we submitted our paper reported a single case of acute necrotizing encephalopathy associated to Covid-19 with RANBP2 pathogenic variants in whom micro hemorrhagic foci were also detected by SWI sequences on MRI.…”

Role of Signaling Pathways in the Viral Life Cycle 2.0

“…The review by Jiang and colleges discusses how mutations in the Ran binding protein 2 (RanBP2 or nucleoporin 358 KDa), a component of the nuclear pore complex, interacts with distinct viruses and affects infection [ 17 ]. RanBP2 is a multifunctional protein that has sumoylation E3-ligase activity, but also participates in other cellular processes including nucleocytoplasmic transport, the trafficking of photoreceptors, mitosis, energy maintenance, myogenesis, mRNA metabolism, and microRNA-induced silencing [ 18 ].…”

“…IAV, parainfluenza virus, human herpes virus 6, respiratory syncytial virus, adenovirus, rhinovirus, rotavirus, and SARS-CoV-2 have all been associated with ANE1. The exact mechanisms by which viruses trigger ANE1 in individuals with RanBP2 mutations remain unclear because viruses can both activate and counteract the action of RanBP2 [ 17 ]. ANE-1-associated mutations in RANBP2 were observed to promote viral infection by facilitating viral uncoating, the nuclear import of viral DNA and proteins, and viral assembly.…”

“…This will result in the overproduction of anti-viral cytokines. SARS-CoV-2 ORF6 was found to modulate the export of cytokine mRNAs in a RanBP2-dependent manner, but another study reported that SARS-CoV-2 infection reduced RanBP2 expression levels (reviewed in [ 17 ]). Further studies are required to disclose the pathogenesis of virus-induced ANE1.…”