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Article ; Online: Molecular mechanism for recognition of the cargo adapter Rab6

Zhao, Xiaoxin / Quintremil, Sebastian / Rodriguez Castro, Estrella D / Cui, Heying / Moraga, David / Wang, Tingyao / Vallee, Richard B / Solmaz, Sozanne R

Life science alliance

2024 Volume 7, Issue 7

Abstract: Rab6 is a key modulator of protein secretion. The dynein adapter Bicaudal D2 (BicD2) recruits the motors cytoplasmic dynein and kinesin-1 to ... ...

Abstract	Rab6 is a key modulator of protein secretion. The dynein adapter Bicaudal D2 (BicD2) recruits the motors cytoplasmic dynein and kinesin-1 to Rab6
MeSH term(s)	rab GTP-Binding Proteins/metabolism ; rab GTP-Binding Proteins/genetics ; Humans ; Dyneins/metabolism ; Dyneins/chemistry ; Protein Binding ; Binding Sites ; Kinesins/metabolism ; Kinesins/chemistry ; Kinesins/genetics ; Mutation ; Microtubule-Associated Proteins/metabolism ; Microtubule-Associated Proteins/chemistry ; Protein Transport ; Models, Molecular ; Guanosine Triphosphate/metabolism
Chemical Substances	Rab6 protein ; rab GTP-Binding Proteins (EC 3.6.5.2) ; BICD2 protein, human ; Dyneins (EC 3.6.4.2) ; Kinesins (EC 3.6.4.4) ; Microtubule-Associated Proteins ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2024-05-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302430
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Roles of the multivalent dynein adaptors BicD2 and RILP in neurons.

Vallee, Richard B / Yi, Julie / Quintremil, Sebastian / Khobrekar, Noopur

Neuroscience letters

2021 Volume 752, Page(s) 135796

Abstract: Cytoplasmic dynein is responsible for all forms of retrograde transport in neurons and other cells. Work over several years has led to the identification of a class of coiled-coil domain containing "adaptor" proteins that are responsible for expanding ... ...

Abstract	Cytoplasmic dynein is responsible for all forms of retrograde transport in neurons and other cells. Work over several years has led to the identification of a class of coiled-coil domain containing "adaptor" proteins that are responsible for expanding dynein's range of cargo interactions, as well as regulating dynein motor behavior. This brief review focuses first on the BicD family of adaptor proteins, which clearly serve to expand the number of dynein cargo interactions. RILP, another adaptor protein, also interacts with multiple proteins. Surprisingly, this is to mediate a series of steps within a common pathway, higher eukaryotic autophagy. These distinct features have important implications for understanding the full range of dynein adaptor functions.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Autophagy ; Humans ; Microfilament Proteins/metabolism ; Microtubule-Associated Proteins/metabolism ; Molecular Chaperones/metabolism ; Nerve Tissue Proteins/metabolism ; Neurons/metabolism ; Nuclear Pore Complex Proteins/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; BICD2 protein, human ; Microfilament Proteins ; Microtubule-Associated Proteins ; Molecular Chaperones ; Nerve Tissue Proteins ; Nuclear Pore Complex Proteins ; RILP protein, human ; SYNE2 protein, human ; ran-binding protein 2
Language	English
Publishing date	2021-03-02
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	194929-9
ISSN	1872-7972 ; 0304-3940
ISSN (online)	1872-7972
ISSN	0304-3940
DOI	10.1016/j.neulet.2021.135796
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Zs.A 1166: Show issues

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Article ; Online: Nesprin-2 Recruitment of BicD2 to the Nuclear Envelope Controls Dynein/Kinesin-Mediated Neuronal Migration In Vivo.

Gonçalves, João Carlos / Quintremil, Sebastian / Yi, Julie / Vallee, Richard B

Current biology : CB

2020 Volume 30, Issue 16, Page(s) 3116–3129.e4

Abstract: Vertebrate brain development depends on a complex program of cell proliferation and migration. Post-mitotic neuronal migration in the developing cerebral cortex involves Nesprin-2, which recruits cytoplasmic dynein, kinesin, and actin to the nuclear ... ...

Abstract	Vertebrate brain development depends on a complex program of cell proliferation and migration. Post-mitotic neuronal migration in the developing cerebral cortex involves Nesprin-2, which recruits cytoplasmic dynein, kinesin, and actin to the nuclear envelope (NE) in other cell types. However, the relative importance of these interactions in neurons has remained poorly understood. To address these issues, we performed in utero electroporation into the developing rat brain to interfere with Nesprin-2 function. We find that an ∼100-kDa "mini" form of the ∼800-kDa Nesprin-2 protein, which binds dynein and kinesin, is sufficient, remarkably, to support neuronal migration. In contrast to dynein's role in forward nuclear migration in these cells, we find that kinesin-1 inhibition accelerates neuronal migration, suggesting a novel role for the opposite-directed motor proteins in regulating migration velocity. In contrast to studies in fibroblasts, the actin-binding domain of Nesprin-2 was dispensable for neuronal migration. We find further that, surprisingly, the motor proteins interact with Nesprin-2 through the dynein/kinesin "adaptor" BicD2, both in neurons and in non-mitotic fibroblasts. Furthermore, mutation of the Nesprin-2 LEWD sequence, implicated in nuclear envelope kinesin recruitment in other systems, interferes with BicD2 binding. Although disruption of the Nesprin-2/BicD2 interaction severely inhibited nuclear movement, centrosome advance proceeded unimpeded, supporting an independent mechanism for centrosome advance. Our data together implicate Nesprin-2 as a novel and fundamentally important form of BicD2 cargo and help explain BicD2's role in neuronal migration and human disease.
MeSH term(s)	Animals ; Biological Transport ; Cell Movement ; Cell Nucleus/genetics ; Dyneins/genetics ; Dyneins/metabolism ; Female ; HeLa Cells ; Humans ; Kinesins/genetics ; Kinesins/metabolism ; Mice ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurons/cytology ; Neurons/physiology ; Nuclear Envelope/genetics ; Nuclear Envelope/metabolism ; Protein Binding ; Rats ; Rats, Sprague-Dawley
Chemical Substances	BICD2 protein, human ; Microfilament Proteins ; Microtubule-Associated Proteins ; Nerve Tissue Proteins ; SYNE2 protein, human ; Dyneins (EC 3.6.4.2) ; Kinesins (EC 3.6.4.4)
Language	English
Publishing date	2020-07-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2020.05.091
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Zs.A 3208: Show issues

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Article ; Online: The Dynein Adaptor RILP Controls Neuronal Autophagosome Biogenesis, Transport, and Clearance.

Khobrekar, Noopur V / Quintremil, Sebastian / Dantas, Tiago J / Vallee, Richard B

Developmental cell

2020 Volume 53, Issue 2, Page(s) 141–153.e4

Abstract: Autophagy plays critical roles in neurodegeneration and development, but how this pathway is organized and regulated in neurons remains poorly understood. Here, we find that the dynein adaptor RILP is essential for retrograde transport of neuronal ... ...

Abstract	Autophagy plays critical roles in neurodegeneration and development, but how this pathway is organized and regulated in neurons remains poorly understood. Here, we find that the dynein adaptor RILP is essential for retrograde transport of neuronal autophagosomes, and surprisingly, their biogenesis as well. We find that induction of autophagy by mTOR inhibition specifically upregulates RILP expression and its localization to autophagosomes. RILP depletion or mutations in its LC3-binding LIR motifs strongly decrease autophagosome numbers suggesting an unexpected RILP role in autophagosome biogenesis. We find that RILP also interacts with ATG5 on isolation membranes, precluding premature dynein recruitment and autophagosome transport. RILP inhibition impedes autophagic turnover and causes p62/sequestosome-1 aggregation. Together, our results identify an mTOR-responsive neuronal autophagy pathway, wherein RILP integrates the processes of autophagosome biogenesis and retrograde transport to control autophagic turnover. This pathway has important implications for understanding how autophagy contributes to neuronal function, development, and disease.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Autophagosomes ; Autophagy ; Autophagy-Related Protein 5/genetics ; Autophagy-Related Protein 5/metabolism ; Biological Transport ; Dyneins/metabolism ; HeLa Cells ; Humans ; Male ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Neurons/cytology ; Neurons/physiology ; Rats ; Rats, Sprague-Dawley ; TOR Serine-Threonine Kinases/genetics ; TOR Serine-Threonine Kinases/metabolism ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; rab7 GTP-Binding Proteins
Chemical Substances	Adaptor Proteins, Signal Transducing ; Atg5 protein, rat ; Autophagy-Related Protein 5 ; LC3 protein, rat ; Microtubule-Associated Proteins ; RILP protein, rat ; rab7 GTP-Binding Proteins ; mTOR protein, rat (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Dyneins (EC 3.6.4.2) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2054967-2
ISSN	1878-1551 ; 1534-5807
ISSN (online)	1878-1551
ISSN	1534-5807
DOI	10.1016/j.devcel.2020.03.011
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Zs.A 5742: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 76: Show issues

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Article ; Online: Cardiovascular Disease: A Target for the Pharmacological Effects of Quercetin.

Gormaz, Juan Guillermo / Quintremil, Sebastian / Rodrigo, Ramon

Current topics in medicinal chemistry

2015 Volume 15, Issue 17, Page(s) 1735–1742

Abstract: Quercetin, a prominent dietary antioxidant present in vegetables, especially onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compounds could be important mediators of the ... ...

Abstract	Quercetin, a prominent dietary antioxidant present in vegetables, especially onions, fruits, highlighting apples and berries, wine and tea, belongs to a group of plant derived heterocyclic polyphenols. These compounds could be important mediators of the biological actions attributed to healthy diets. Chemically, quercetin is a type of flavonoid that specifically belongs to the flavonols group. It naturally occurs either as glycoside or aglycone, both of which have biological activity. Many of the natural sources of quercetin are included in the Mediterranean diet, a dietary habit associated with a decrease of cardiovascular diseases. During the last years, several researches have reported effects consistent with pharmacological applications of quercetin in cardiovascular diseases, such as atherosclerosis, ischemia-reperfusion injury, cardiotoxicity, and hypertension, among others. In this review, the pathways and molecules involved in the beneficial effects of quercetin are summarized. In addition, a scope of the new insights concerning quercetin pharmacokinetics, pharmacodynamics and bioavailability are presented. The mechanisms whereby quercetin exerts its effects have not been fully elucidated. However, interesting results have been obtained from early clinical studies involving cardioprotection by quercetin, but much knowledge is still lacking in the field of its bioavailability to improve the clinical application of this flavonol. This study presents evidence supporting the point of view that quercetin should be considered a potential therapeutic agent against cardiovascular diseases, giving rise to novel applications in their prevention and treatment.
MeSH term(s)	Antioxidants/chemistry ; Antioxidants/therapeutic use ; Cardiovascular Diseases/drug therapy ; Humans ; Molecular Structure ; Quercetin/chemistry ; Quercetin/pharmacology
Chemical Substances	Antioxidants ; Quercetin (9IKM0I5T1E)
Language	English
Publishing date	2015-02-24
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2064823-6
ISSN	1873-4294 ; 1568-0266
ISSN (online)	1873-4294
ISSN	1568-0266
DOI	10.2174/1568026615666150427124357
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Zs.A 5572: Show issues

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Article ; Online: Tax and Semaphorin 4D Released from Lymphocytes Infected with Human Lymphotropic Virus Type 1 and Their Effect on Neurite Growth.

Quintremil, Sebastián / Alberti, Carolina / Rivera, Matías / Medina, Fernando / Puente, Javier / Cartier, Luis / Ramírez, Eugenio / Tanaka, Yuetsu / Valenzuela, M Antonieta

AIDS research and human retroviruses

2016 Volume 32, Issue 1, Page(s) 68–79

Abstract: Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without ... ...

Abstract	Human lymphotropic virus type 1 (HTLV-1) is a retrovirus causing HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a neurodegenerative central nervous system (CNS) axonopathy. This virus mainly infects CD4(+) T lymphocytes without evidence of neuronal infection. Viral Tax, secreted from infected lymphocytes infiltrated in the CNS, is proposed to alter intracellular pathways related to axonal cytoskeleton dynamics, producing neurological damage. Previous reports showed a higher proteolytic release of soluble Semaphorin 4D (sSEMA-4D) from CD4(+) T cells infected with HTLV-1. Soluble SEMA-4D binds to its receptor Plexin-B1, activating axonal growth collapse pathways in the CNS. In the current study, an increase was found in both SEMA-4D in CD4(+) T cells and sSEMA-4D released to the culture medium of peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients compared to asymptomatic carriers and healthy donors. After a 16-h culture, infected PBMCs showed significantly higher levels of CRMP-2 phosphorylated at Ser(522). The effect was blocked either with anti-Tax or anti-SEMA-4D antibodies. The interaction of Tax and sSEMA-4D was found in secreted medium of PBMCs in patients, which might be associated with a leading role of Tax with the SEMA-4D-Plexin-B1 signaling pathway. In infected PBMCs, the migratory response after transwell assay showed that sSEMA-4D responding cells were CD4(+)Tax(+) T cells with a high CRMP-2 pSer(522) content. In the present study, the participation of Tax-sSEMA-4D in the reduction in neurite growth in PC12 cells produced by MT2 (HTLV-1-infected cell line) culture medium was observed. These results lead to the participation of plexins in the reported effects of infected lymphocytes on neuronal cells.
MeSH term(s)	Animals ; Antibodies, Neutralizing/pharmacology ; Antigens, CD/genetics ; Antigens, CD/metabolism ; Carrier State ; Case-Control Studies ; Cell Movement/drug effects ; Culture Media, Conditioned/pharmacology ; Gene Expression Regulation ; Gene Products, tax/genetics ; Gene Products, tax/metabolism ; Human T-lymphotropic virus 1/genetics ; Human T-lymphotropic virus 1/metabolism ; Humans ; K562 Cells ; Leukocytes, Mononuclear/metabolism ; Leukocytes, Mononuclear/pathology ; Leukocytes, Mononuclear/virology ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Neurites/drug effects ; Neurites/metabolism ; Neurites/ultrastructure ; PC12 Cells ; Paraparesis, Tropical Spastic/genetics ; Paraparesis, Tropical Spastic/metabolism ; Paraparesis, Tropical Spastic/pathology ; Paraparesis, Tropical Spastic/virology ; Primary Cell Culture ; Rats ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; Semaphorins/genetics ; Semaphorins/metabolism ; Signal Transduction
Chemical Substances	Antibodies, Neutralizing ; Antigens, CD ; CD100 antigen ; Culture Media, Conditioned ; Gene Products, tax ; Nerve Tissue Proteins ; PLXNB1 protein, human ; Receptors, Cell Surface ; Semaphorins
Language	English
Publishing date	2016-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/aid.2015.0008
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Zs.A 1928: Show issues

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Article ; Online: Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction.

Vaz-Silva, João / Gomes, Patrícia / Jin, Qi / Zhu, Mei / Zhuravleva, Viktoriya / Quintremil, Sebastian / Meira, Torcato / Silva, Joana / Dioli, Chrysoula / Soares-Cunha, Carina / Daskalakis, Nikolaos P / Sousa, Nuno / Sotiropoulos, Ioannis / Waites, Clarissa L

The EMBO journal

2018 Volume 37, Issue 20

Abstract: Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated ... ...

Abstract	Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Cell Line, Tumor ; Cognitive Dysfunction/genetics ; Cognitive Dysfunction/metabolism ; Cognitive Dysfunction/pathology ; Dependovirus ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism ; Endosomes/genetics ; Endosomes/metabolism ; Endosomes/pathology ; Glucocorticoids/genetics ; Glucocorticoids/metabolism ; HEK293 Cells ; Hippocampus/metabolism ; Hippocampus/pathology ; Humans ; Lysosomes/genetics ; Lysosomes/metabolism ; Lysosomes/pathology ; Neurons/metabolism ; Neurons/pathology ; Proteolysis ; Rats ; Stress, Physiological ; Transduction, Genetic ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	Endosomal Sorting Complexes Required for Transport ; Glucocorticoids ; Mapt protein, rat ; tau Proteins ; Rab35 protein, rat (EC 3.6.1.-) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2018-08-30
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.15252/embj.201899084
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Zs.A 1808: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 100: Show issues

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Article ; Online: Tax secretion from peripheral blood mononuclear cells and Tax detection in plasma of patients with human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis and asymptomatic carriers.

Medina, Fernando / Quintremil, Sebastián / Alberti, Carolina / Godoy, Fabián / Pando, María E / Bustamante, Andrés / Barriga, Andrés / Cartier, Luis / Puente, Javier / Tanaka, Yuetsu / Valenzuela, María A / Ramírez, Eugenio

Journal of medical virology

2016 Volume 88, Issue 3, Page(s) 521–531

Abstract: Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested ... ...

Abstract	Human T-lymphotropic virus-type 1 (HTLV-1) is the etiologic agent of the neurologic disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Tax viral protein plays a critical role in viral pathogenesis. Previous studies suggested that extracellular Tax might involve cytokine-like extracellular effects. We evaluated Tax secretion in 18 h-ex vivo peripheral blood mononuclear cells (PBMCs) cultures from 15 HAM/TSP patients and 15 asymptomatic carriers. Futhermore, Tax plasma level was evaluated from other 12 HAM/TSP patients and 10 asymptomatic carriers. Proviral load and mRNA encoding Tax were quantified by PCR and real-time RT-PCR, respectively. Intracellular Tax in CD4(+)CD25(+) cells occurred in 100% and 86.7% of HAM/TSP patients and asymptomatic carriers, respectively. Percentage of CD4(+)CD25(+) Tax+, proviral load and mRNA encoding Tax were significantly higher in HAM/TSP patients. Western blot analyses showed higher secretion levels of ubiquitinated Tax in HAM/TSP patients than in asymptomatic carriers. In HTLV-1-infected subjects, Western blot of plasma Tax showed higher levels in HAM/TSP patients than in asymptomatic carriers, whereas no Tax was found in non-infected subjects. Immunoprecipitated plasma Tax resolved on SDS-PAGE gave two major bands of 57 and 48 kDa allowing identification of Tax and Ubiquitin peptides by mass spectrometry. Relative percentage of either CD4(+)CD25(+) Tax+ cells, or Tax protein released from PBMCs, or plasma Tax, correlates neither with tax mRNA nor with proviral load. This fact could be explained by a complex regulation of Tax expression. Tax secreted from PBMCs or present in plasma could potentially become a biomarker to distinguish between HAM/TSP patients and asymptomatic carriers.
MeSH term(s)	Adult ; Aged ; Asymptomatic Infections ; Biomarkers/blood ; Carrier State/virology ; Cells, Cultured ; DNA, Viral/analysis ; Electrophoresis, Polyacrylamide Gel ; Female ; Gene Products, tax/blood ; Human T-lymphotropic virus 1/genetics ; Human T-lymphotropic virus 1/physiology ; Humans ; Leukocytes, Mononuclear/virology ; Male ; Middle Aged ; Paraparesis, Tropical Spastic/virology ; Proviruses/genetics ; RNA, Messenger ; Ubiquitination ; Viral Load
Chemical Substances	Biomarkers ; DNA, Viral ; Gene Products, tax ; RNA, Messenger
Language	English
Publishing date	2016-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	752392-0
ISSN	1096-9071 ; 0146-6615
ISSN (online)	1096-9071
ISSN	0146-6615
DOI	10.1002/jmv.24342
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Zs.A 1320: Show issues

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Article ; Online: Tax posttranslational modifications and interaction with calreticulin in MT-2 cells and human peripheral blood mononuclear cells of human T cell lymphotropic virus type-I-associated myelopathy/tropical spastic paraparesis patients.

Medina, Fernando / Quintremil, Sebastian / Alberti, Carolina / Barriga, Andres / Cartier, Luis / Puente, Javier / Ramírez, Eugenio / Ferreira, Arturo / Tanaka, Yuetsu / Valenzuela, Maria Antonieta

AIDS research and human retroviruses

2014 Volume 30, Issue 4, Page(s) 370–379

Abstract: The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted ...

Abstract	The human retrovirus human T cell lymphotropic virus type-I (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Axonal degeneration in HAM/TSP patients occurs without neuron infection, with the secreted viral Tax protein proposed to be involved. We previously found that Tax secreted into the culture medium of MT-2 cells (HTLV-1-infected cell line) produced neurite retraction in neuroblastoma cells differentiated to neuronal type. To assess the relevance of Tax posttranslational modifications on this effect, we addressed the question of whether Tax secreted by MT-2 cells and peripheral blood mononuclear cells (PBMCs) of HTLV-1-infected subjects is modified. The interaction of Tax with calreticulin (CRT) that modulates intracellular Tax localization and secretion has been described. We studied Tax localization and modifications in MT-2 cells and its interaction with CRT. Intracellular Tax in MT-2 cells was assessed by flow cytometry, corresponding mainly to a 71-kDa protein followed by western blot. This protein reported as a chimera with gp21 viral protein-confirmed by mass spectrometry-showed no ubiquitination or SUMOylation. The Tax-CRT interaction was determined by confocal microscopy and coimmunoprecipitation. Extracellular Tax from HAM/TSP PBMCs is ubiquitinated according to western blot, and its interaction with CRT was shown by coimmunoprecipitation. A positive correlation between Tax and CRT secretion was observed in HAM/TSP PBMCs and asymptomatic carriers. For both proteins inhibitors and activators of secretion showed secretion through the endoplasmic reticulum-Golgi complex. Tax, present in PBMC culture medium, produced neurite retraction in differentiated neuroblastoma cells. These results suggest that Tax, whether ubiquitinated or not, is active for neurite retraction.
MeSH term(s)	Blotting, Western ; Calreticulin/metabolism ; Cells, Cultured ; Flow Cytometry ; Gene Products, tax/metabolism ; HTLV-I Infections/immunology ; HTLV-I Infections/virology ; Host-Pathogen Interactions ; Human T-lymphotropic virus 1/physiology ; Humans ; Immunoprecipitation ; Leukocytes, Mononuclear/immunology ; Leukocytes, Mononuclear/virology ; Microscopy, Confocal ; Protein Interaction Mapping ; Protein Processing, Post-Translational
Chemical Substances	CALR protein, human ; Calreticulin ; Gene Products, tax ; tax protein, Human T-lymphotrophic virus 1
Language	English
Publishing date	2014-01-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639130-8
ISSN	1931-8405 ; 0889-2229
ISSN (online)	1931-8405
ISSN	0889-2229
DOI	10.1089/AID.2013.0036
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