Targeting deoxyhypusine hydroxylase activity impairs cap-independent translation initiation driven by the 5'untranslated region of the HIV-1, HTLV-1, and MMTV mRNAs

Cáceres, C. Joaquín; Angulo, Jenniffer; Contreras, Nataly; Pino, Karla; Vera-Otárola, Jorge; López-Lastra, Marcelo

doi:10.1016/j.antiviral.2016.09.006

Cited by 29 publications

(30 citation statements)

References 87 publications

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“…EIF5A also regulates mitochondrial respiration via initiation from alternative start codons. In addition, EIF5A restricts RNA virus infections [22, 55, 64, 78, 101, 110, 112, 113, 125, 148, 152, 164, 235]. It is important to note in this context that ATXN2 is cleaved by Coxsackie-virus and Polio-virus, during their optimized efforts to diminish host cell defenses against invading viral RNA [84].…”

Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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Large polyglutamine expansions in Ataxin-2 (ATXN2) cause multi-system nervous atrophy in Spinocerebellar Ataxia type 2 (SCA2). Intermediate size expansions carry a risk for selective motor neuron degeneration, known as Amyotrophic Lateral Sclerosis (ALS). Conversely, the depletion of ATXN2 prevents disease progression in ALS. Although ATXN2 interacts directly with RNA, and in ALS pathogenesis there is a crucial role of RNA toxicity, the affected functional pathways remain ill defined. Here, we examined an authentic SCA2 mouse model with Atxn2-CAG100-KnockIn for a first definition of molecular mechanisms in spinal cord pathology.Neurophysiology of lower limbs detected sensory neuropathy rather than motor denervation. Triple immunofluorescence demonstrated cytosolic ATXN2 aggregates sequestrating TDP43 and TIA1 from the nucleus. In immunoblots, this was accompanied by elevated CASP3, RIPK1 and PQBP1 abundance. RT-qPCR showed increase of Grn, Tlr7 and Rnaset2 mRNA versus Eif5a2, Dcp2, Uhmk1 and Kif5a decrease. These SCA2 findings overlap well with known ALS features. Similar to other ataxias and dystonias, decreased mRNA levels for Unc80, Tacr1, Gnal, Ano3, Kcna2, Elovl5 and Cdr1 contrasted with Gpnmb increase. Preterminal stage tissue showed strongly activated microglia containing ATXN2 aggregates, with parallel astrogliosis. Global transcriptome profiles from stages of incipient motor deficit versus preterminal age identified molecules with progressive downregulation, where a cluster of cholesterol biosynthesis enzymes including Dhcr24, Msmo1, Idi1and Hmgcs1 was prominent. Gas chromatography demonstrated a massive loss of crucial cholesterol precursor metabolites. Overall, the ATXN2 protein aggregation process affects diverse subcellular compartments, in particular stress granules, endoplasmic reticulum and receptor tyrosine kinase signaling. These findings identify new targets and potential biomarkers for neuroprotective therapies. Introduction:Within the dynamic research field into neurodegenerative disorders, the rare monogenic variant SCA2 (Spinocerebellar Ataxia type 2) gained much attention over the past decade, since its pathogenesis is intertwined with the motor neuron diseases ALS/FTLD (Amyotrophic Lateral Sclerosis / Fronto-Temporal Lobar Dementia) and with extrapyramidal syndromes such as Parkinson/PSP (Progressive Supranuclear Palsy). Particularly in the past year, it received massive interest since antisense-oligonucleotides were shown to effectively prevent the disease in mouse models, with clinical trials now being imminent. Still, there is an urgent unmet need to define the molecular events of pathogenesis and to identify biomarkers of progression in SCA2 patients, which reflect therapeutic benefits much more rapidly than clinical rating scales, brain imaging volumetry or neurophysiology measures.SCA2 was first described as separate entity in Indian patients, based on the characteristic early slowing of eye saccadic movements [222]. A molecularly homogeneous founder population of ~1,000 patients in...

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Section: Resultsmentioning

confidence: 99%

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Canet-Pons

Sen

Arsovic

et al. 2019

Preprint

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“…A common feature of the activity of retrovirus IRES elements is their requirement for eIF5A hypusination ( Caceres et al, 2016a ). Hypusine is a post-translational modification of eIF5A, which depends on the deoxyhypusine synthase and the deoxyhypusine hydroxylase.…”

Section: Internal Initiation Mechanisms: Rna Structural Motifs Involvmentioning

confidence: 99%

Insights into Structural and Mechanistic Features of Viral IRES Elements

et al. 2018

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Internal ribosome entry site (IRES) elements are cis-acting RNA regions that promote internal initiation of protein synthesis using cap-independent mechanisms. However, distinct types of IRES elements present in the genome of various RNA viruses perform the same function despite lacking conservation of sequence and secondary RNA structure. Likewise, IRES elements differ in host factor requirement to recruit the ribosomal subunits. In spite of this diversity, evolutionarily conserved motifs in each family of RNA viruses preserve sequences impacting on RNA structure and RNA–protein interactions important for IRES activity. Indeed, IRES elements adopting remarkable different structural organizations contain RNA structural motifs that play an essential role in recruiting ribosomes, initiation factors and/or RNA-binding proteins using different mechanisms. Therefore, given that a universal IRES motif remains elusive, it is critical to understand how diverse structural motifs deliver functions relevant for IRES activity. This will be useful for understanding the molecular mechanisms beyond cap-independent translation, as well as the evolutionary history of these regulatory elements. Moreover, it could improve the accuracy to predict IRES-like motifs hidden in genome sequences. This review summarizes recent advances on the diversity and biological relevance of RNA structural motifs for viral IRES elements.

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“…COS-7 (ATTC CRL-1651), HeLa (ATTC CCL-2TM) and HEK 293T (ATCC CRL-11268) cells were grown as described in ( 15 , 23 , 24 ). Reagents for cell culture were purchased from HyClone, GE Healthcare Life Sciences (Logan, Utah, USA).…”

Section: Methodsmentioning

confidence: 99%

“…For the poliovirus HRV 2A protease experiments COS-7 cells were cotransfected with 200 ng of the dl sHBZ 5′UTR plasmid and 500 ng of the HRV p2A-wt or HRV p2A-mut per well in a 24-well plate. Deferiprone (DFP) (CAS: 30652–11-0; #379409; Sigma-Aldrich) was used as described in ( 23 ). In these experiments 200 ng of dl sHBZ 5′UTR, dl HTLV-1 IRES or dl PV IRES were co-transfected with 50 ng of pcDNA3.1-LacZ in COS-7 cells.…”

Section: Methodsmentioning

confidence: 99%

Non-canonical translation initiation of the spliced mRNA encoding the human T-cell leukemia virus type 1 basic leucine zipper protein

Cáceres

Angulo

Lowy

et al. 2018

Nucleic Acids Research

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Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL). The HTLV-1 basic leucine zipper protein (HBZ) is expressed in all cases of ATL and is directly associated with virus pathogenicity. The two isoforms of the HBZ protein are synthesized from antisense messenger RNAs (mRNAs) that are either spliced (sHBZ) or unspliced (usHBZ) versions of the HBZ transcript. The sHBZ and usHBZ mRNAs have entirely different 5′untranslated regions (5′UTR) and are differentially expressed in cells, with the sHBZ protein being more abundant. Here, we show that differential expression of the HBZ isoforms is regulated at the translational level. Translation initiation of the usHBZ mRNA relies on a cap-dependent mechanism, while the sHBZ mRNA uses internal initiation. Based on the structural data for the sHBZ 5′UTR generated by SHAPE in combination with 5′ and 3′ deletion mutants, the minimal region harboring IRES activity was mapped to the 5′end of the sHBZ mRNA. In addition, the sHBZ IRES recruited the 40S ribosomal subunit upstream of the initiation codon, and IRES activity was found to be dependent on the ribosomal protein eS25 and eIF5A.

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Targeting deoxyhypusine hydroxylase activity impairs cap-independent translation initiation driven by the 5'untranslated region of the HIV-1, HTLV-1, and MMTV mRNAs

Cited by 29 publications

References 87 publications

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

Insights into Structural and Mechanistic Features of Viral IRES Elements

Non-canonical translation initiation of the spliced mRNA encoding the human T-cell leukemia virus type 1 basic leucine zipper protein

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