Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA function

Deshmukh, Prachi; Singh, Aditi; Khuperkar, Deepak; Joseph, Jomon

doi:10.1016/j.bbrc.2021.04.027

Cited by 11 publications

(11 citation statements)

References 23 publications

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“…Sumoylation by NUP358 stabilises AGO1 by antagonising its ubiquitination and promotes miRNA‐mediated silencing of IL6 mRNA [128]. NUP358 furthermore interacts with GW182/TNRC6, another constituent of the miRISC [134], emphasising the link between NUP358 and the miRNA pathway. ANE1‐related mutations in NUP35 8 impair the interaction between NUP358 and the AGO complex, thereby compromising miRNA‐mediated silencing of IL6 , which may lead to cytokine over‐production and ultimately the ANE1‐associated neurological manifestations [128,134].…”

Section: Disorders Related To the Cytoplasmic Filament Nucleoporin Ne...mentioning

confidence: 99%

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Jühlen,

Fahrenkrog

2023

FEBS Letters

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The subcellular compartmentalisation of eukaryotic cells requires selective exchange between the cytoplasm and the nucleus. Intact nucleocytoplasmic transport is vital for normal cell function and mutations in the executing machinery have been causally linked to human disease. Central players in nucleocytoplasmic exchange are nuclear pore complexes (NPCs), which are built from ~30 distinct proteins collectively termed nucleoporins. Aberrant nucleoporin expression was detected in human cancers and autoimmune diseases since quite some time, while it was through the increasing use of next generation sequencing that mutations in nucleoporin genes associated with mainly rare hereditary diseases were revealed. The number of newly identified mutations is steadily increasing, as is the number of diseases. Mutational hotspots have emerged: mutations in the scaffold nucleoporins seemingly affect primarily inner organs, such as heart, kidney, and ovaries, whereas genetic alterations in peripheral, cytoplasmic nucleoporins affect primarily the central nervous system and development. In this review, we summarise latest insights on altered nucleoporin function in the context of human hereditary disorders, with a focus on those where mechanistic insights are beginning to emerge.

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Section: Disorders Related To the Cytoplasmic Filament Nucleoporin Ne...mentioning

confidence: 99%

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

Jühlen,

Fahrenkrog

2023

FEBS Letters

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“…In agreement with this idea, RanBP2-depletion has been shown to reduce the number of P-bodies, which are cytoplasmic foci that have been implicated in microRNA-silencing [ 31 , 105 ]. Moreover, it has been recently shown that ANE1 mutations disrupt the association between RanBP2 and the Argonaute binding partner GW182 [ 32 ]. Despite this, a form of RanBP2 containing three of the ANE1-associated mutations (Thr585Met, Thr653Ile, and Ile656Val) rescued Argonaute1-dependent silencing of the IL6 mRNA in human osteosarcoma cells [ 30 ].…”

Section: Pathogenesis Of Ane1: Roles Of Ranbp2 In Ane1mentioning

confidence: 99%

“…The formation of the tight RanBP2/SUMO-RanGAP1/Ubc9 complex at the cytoplasmic filaments of the NPC is essential for the SUMO E3-ligase activity of RanBP2 [ 14 ]. Aside from mediating sumoylation, RanBP2 has been implicated in many aspects of cellular processes, including nucleocytoplasmic transport [ 15 , 16 , 17 , 18 ], trafficking of photoreceptors [ 19 , 20 ], glucose metabolism [ 21 ], attachment of microtubules to kinetochores during mitosis [ 22 , 23 , 24 , 25 ], myogenesis [ 26 , 27 ], and mRNA metabolism [ 18 , 28 , 29 ], as well as microRNA-induced silencing [ 30 , 31 , 32 , 33 ]. Beyond the nuclear pore, RanBP2 also appears to form cytosolic aggregates, which may include annulate lamellae and/or some other biomolecular condensates [ 31 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

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

Jiang

Wang

Palazzo

et al. 2022

IJMS

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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.

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“…GW182 proteins are components of RISC and responsible for recruiting decapping enzymes, deadenylases and translation inhibitory proteins to mRNAs silenced by RISC [ 79 , 80 ]. Interestingly, the Joseph group found that the N-terminal region of RanBP2/Nup358 binds to GW182 and that this is disrupted by ANE mutations [ 81 ], although the Palazzo group noted that a mutant form of RanBP2/Nup358 harboring three of the ANE mutations is still able to downregulate the Interleukin 6 mRNA [ 72 ]. Nevertheless, this work provides a potential model of how RanBP2/Nup358 dysregulation could alter cytokine production.…”

Section: Ranbp2/nup358 and The Innate Immune Responsementioning

confidence: 99%

Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy

Palazzo

Joseph

Lim

et al. 2022

Nucleus

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Dominant missense mutations in RanBP2/Nup358 cause Acute Necrotizing Encephalopathy (ANE), a pediatric disease where seemingly healthy individuals develop a cytokine storm that is restricted to the central nervous system in response to viral infection. Untreated, this condition leads to seizures, coma, long-term neurological damage and a high rate of mortality. The exact mechanism by which RanBP2 mutations contribute to the development of ANE remains elusive. In November 2021, a number of clinicians and basic scientists presented their work on this disease and on the interactions between RanBP2/Nup358, viral infections, the innate immune response and other cellular processes.

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Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA function

Cited by 11 publications

References 23 publications

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

From the sideline: Tissue‐specific nucleoporin function in health and disease, an update

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

Workshop on RanBP2/Nup358 and acute necrotizing encephalopathy

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