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  1. Article ; Online: Unconventional role of Rab4 in the secretory pathway in Leishmania.

    Ansari, Irshad / Singh, Amir Kumar / Kapoor, Anjali / Mukhopadhyay, Amitabha

    Biochimica et biophysica acta. Molecular cell research

    2024  Volume 1871, Issue 4, Page(s) 119687

    Abstract: Leishmania donovani is an auxotroph for heme. Parasite acquires heme by clathrin-mediated endocytosis of hemoglobin by specific receptor. However, the regulation of receptor recycling pathway is not known in Leishmania. Here, we have cloned, expressed ... ...

    Abstract Leishmania donovani is an auxotroph for heme. Parasite acquires heme by clathrin-mediated endocytosis of hemoglobin by specific receptor. However, the regulation of receptor recycling pathway is not known in Leishmania. Here, we have cloned, expressed and characterized the Rab4 homologue from L. donovani. We have found that LdRab4 localizes in both early endosomes and Golgi in L. donovani. To understand the role of LdRab4 in L. donovani, we have generated transgenic parasites overexpressing GFP-LdRab4:WT, GFP-LdRab4:Q67L, and GFP-LdRab4:S22N. Our results have shown that overexpression of GFP-LdRab4:Q67L or GFP-LdRab4:S22N does not alter the cell surface localization of hemoglobin receptor in L. donovani. Surprisingly, we have found that overexpression of GFP-LdRab4:S22N significantly blocks the transport of Ldgp63 to the cell surface whereas the trafficking of Ldgp63 is induced to the cell surface in GFP-LdRab4:WT and GFP-LdRab4:Q67L overexpressing parasites. Consequently, we have found significant inhibition of gp63 secretion by GFP-LdRab4:S22N overexpressing parasites whereas secretion of Ldgp63 is enhanced in GFP-LdRab4:WT and GFP-LdRab4:Q67L overexpressing parasites in comparison to untransfected control parasites. Moreover, we have found that survival of transgenic parasites overexpressing GFP-LdRab4:S22N is severely compromised in macrophages in comparison to GFP-LdRab4:WT and GFP-LdRab4:Q67L expressing parasites. These results demonstrated that LdRab4 unconventionally regulates the secretory pathway in L. donovani.
    MeSH term(s) Animals ; Secretory Pathway ; Leishmania donovani/genetics ; Animals, Genetically Modified/metabolism ; Carrier Proteins/metabolism ; Hemoglobins/metabolism ; Heme/metabolism
    Chemical Substances Carrier Proteins ; Hemoglobins ; Heme (42VZT0U6YR)
    Language English
    Publishing date 2024-02-10
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2024.119687
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  2. Article ; Online: CHIP stabilizes amyloid precursor protein via proteasomal degradation and p53-mediated trans-repression of β-secretase.

    Singh, Amir Kumar / Pati, Uttam

    Aging cell

    2015  Volume 14, Issue 4, Page(s) 595–604

    Abstract: In patient with Alzheimer's disease (AD), deposition of amyloid-beta Aβ, a proteolytic cleavage of amyloid precursor protein (APP) by β-secretase/BACE1, forms senile plaque in the brain. BACE1 activation is caused due to oxidative stresses and ... ...

    Abstract In patient with Alzheimer's disease (AD), deposition of amyloid-beta Aβ, a proteolytic cleavage of amyloid precursor protein (APP) by β-secretase/BACE1, forms senile plaque in the brain. BACE1 activation is caused due to oxidative stresses and dysfunction of ubiquitin-proteasome system (UPS), which is linked to p53 inactivation. As partial suppression of BACE1 attenuates Aβ generation and AD-related pathology, it might be an ideal target for AD treatment. We have shown that both in neurons and in HEK-APP cells, BACE1 is a new substrate of E3-ligase CHIP and an inverse relation exists between CHIP and BACE1 level. CHIP inhibits ectopic BACE1 level by promoting its ubiquitination and proteasomal degradation, thus reducing APP processing; it stabilizes APP in neurons, thus reducing Aβ. CHIP(U) (box) domain physically interacts with BACE1; however, both U-box and TPR domain are essential for ubiquitination and degradation of BACE1. Further, BACE1 is a downstream target of p53 and overexpression of p53 decreases BACE1 level. In HEK-APP cells, CHIP is shown to negatively regulate BACE1 promoter through stabilization of p53's DNA-binding conformation and its binding upon 5' UTR element (+127 to +150). We have thus discovered that CHIP regulates p53-mediated trans-repression of BACE1 at both transcriptional and post-translational level. We propose that a CHIP-BACE1-p53 feedback loop might control APP stabilization, which could further be utilized for new therapeutic intervention in AD.
    MeSH term(s) Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Aspartic Acid Endopeptidases/genetics ; Aspartic Acid Endopeptidases/metabolism ; Cell Line, Tumor ; Cerebral Cortex/cytology ; Cerebral Cortex/metabolism ; Feedback, Physiological ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Neurons/cytology ; Neurons/metabolism ; Primary Cell Culture ; Promoter Regions, Genetic ; Proteasome Endopeptidase Complex/metabolism ; Protein Biosynthesis ; Protein Stability ; Proteolysis ; Rats ; Signal Transduction ; Transcription, Genetic ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances APP protein, human ; Amyloid beta-Protein Precursor ; Tumor Suppressor Protein p53 ; STUB1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; BACE1 protein, human (EC 3.4.23.46) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2015-08
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2113083-8
    ISSN 1474-9726 ; 1474-9718
    ISSN (online) 1474-9726
    ISSN 1474-9718
    DOI 10.1111/acel.12335
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6581: Show issues Location:
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  3. Article ; Online: RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation.

    Singh, Amir Kumar / Kumar, Ritesh / Yin, Jianyi / Brooks Ii, John F / Kathania, Mahesh / Mukherjee, Sandip / Kumar, Jitendra / Conlon, Kevin P / Basrur, Venkatesha / Chen, Zhe / Han, Xianlin / Hooper, Lora V / Burstein, Ezra / Venuprasad, K

    Nature communications

    2023  Volume 14, Issue 1, Page(s) 4972

    Abstract: Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the ... ...

    Abstract Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.
    MeSH term(s) Humans ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Virulence ; Th17 Cells ; Inflammation ; Colon
    Chemical Substances Nuclear Receptor Subfamily 1, Group F, Member 3
    Language English
    Publishing date 2023-08-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-023-40622-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cutting Edge: Hypoxia-Induced Ubc9 Promoter Hypermethylation Regulates IL-17 Expression in Ulcerative Colitis.

    Kumar, Ritesh / Singh, Amir Kumar / Starokadomskyy, Petro / Luo, Weibo / Theiss, Arianne L / Burstein, Ezra / Venuprasad, K

    Journal of immunology (Baltimore, Md. : 1950)

    2021  Volume 206, Issue 5, Page(s) 936–940

    Abstract: Dysregulated IL-17 expression is central to the pathogenesis of several inflammatory disorders, including ulcerative colitis. We have shown earlier that SUMOylation of ROR-γt, the transcription factor for IL-17, regulates colonic inflammation. In this ... ...

    Abstract Dysregulated IL-17 expression is central to the pathogenesis of several inflammatory disorders, including ulcerative colitis. We have shown earlier that SUMOylation of ROR-γt, the transcription factor for IL-17, regulates colonic inflammation. In this study, we show that the expression of Ubc9, the E2 enzyme that targets ROR-γt for SUMOylation, is significantly reduced in the colonic mucosa of ulcerative colitis patients. Mechanistically, we demonstrate that hypoxia-inducible factor 1α (HIF-1α) binds to a CpG island within the Ubc9 gene promoter, resulting in its hypermethylation and reduced Ubc9 expression. CRISPR-Cas9-mediated inhibition of HIF-1α normalized Ubc9 and attenuated IL-17 expression in Th17 cells and reduced diseases severity in
    MeSH term(s) Animals ; Colitis, Ulcerative/genetics ; Colitis, Ulcerative/pathology ; Colon/pathology ; DNA Methylation/genetics ; Humans ; Hypoxia/genetics ; Hypoxia/pathology ; Inflammation/genetics ; Inflammation/pathology ; Interleukin-17/genetics ; Intestinal Mucosa/pathology ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3/genetics ; Promoter Regions, Genetic/genetics ; Th17 Cells ; Ubiquitin-Conjugating Enzymes/genetics
    Chemical Substances Interleukin-17 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; ubiquitin-conjugating enzyme UBC9 (EC 6.3.2.-)
    Language English
    Publishing date 2021-01-27
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2000015
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    Ud II Zs.37: Show issues Location:
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  5. Article ; Online: SUMOylation of ROR-γt inhibits IL-17 expression and inflammation via HDAC2.

    Singh, Amir Kumar / Khare, Prashant / Obaid, Abeer / Conlon, Kevin P / Basrur, Venkatesha / DePinho, Ronald A / Venuprasad, K

    Nature communications

    2018  Volume 9, Issue 1, Page(s) 4515

    Abstract: Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined. Here ...

    Abstract Dysregulated ROR-γt-mediated IL-17 transcription is central to the pathogenesis of several inflammatory disorders, yet the molecular mechanisms that govern the transcription factor activity of ROR-γt in the regulation of IL-17 are not fully defined. Here we show that SUMO-conjugating enzyme Ubc9 interacts with a conserved GKAE motif in ROR-γt to induce SUMOylation of ROR-γt and suppress IL-17 expression. Th17 cells expressing SUMOylation-defective ROR-γt are highly colitogenic upon transfer to Rag1
    MeSH term(s) Animals ; Colitis/genetics ; Colitis/immunology ; Colitis/metabolism ; Histone Deacetylase 2/immunology ; Histone Deacetylase 2/metabolism ; Homeodomain Proteins/genetics ; Inflammation ; Interleukin-17/immunology ; Interleukin-17/metabolism ; Mice ; Mice, Knockout ; Nuclear Receptor Subfamily 1, Group F, Member 3/immunology ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Sumoylation/immunology ; Th17 Cells/immunology ; Ubiquitin-Conjugating Enzymes/metabolism
    Chemical Substances Homeodomain Proteins ; Il17a protein, mouse ; Interleukin-17 ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; RAG-1 protein (128559-51-3) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Hdac2 protein, mouse (EC 3.5.1.98) ; Histone Deacetylase 2 (EC 3.5.1.98) ; ubiquitin-conjugating enzyme UBC9 (EC 6.3.2.-)
    Language English
    Publishing date 2018-10-30
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-018-06924-5
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  6. Article ; Online: p53 Amino-terminus region (1-125) stabilizes and restores heat denatured p53 wild phenotype.

    Sharma, Anuj Kumar / Ali, Amjad / Gogna, Rajan / Singh, Amir Kumar / Pati, Uttam

    PloS one

    2009  Volume 4, Issue 10, Page(s) e7159

    Abstract: Background: The intrinsically disordered N-ter domain (NTD) of p53 encompasses approximately hundred amino acids that contain a transactivation domain (1-73) and a proline-rich domain (64-92) and is responsible for transactivation function and apoptosis. ...

    Abstract Background: The intrinsically disordered N-ter domain (NTD) of p53 encompasses approximately hundred amino acids that contain a transactivation domain (1-73) and a proline-rich domain (64-92) and is responsible for transactivation function and apoptosis. It also possesses an auto-inhibitory function as its removal results in remarkable reduction in dissociation of p53 from DNA.
    Principal findings/methodology: In this report, we have discovered that p53-NTD spanning amino acid residues 1-125 (NTD125) interacted with WT p53 and stabilized its wild type conformation under physiological and elevated temperatures, both in vitro and in cellular systems. NTD125 prevented irreversible thermal aggregation of heat denatured p53, enhanced p21-5'-DBS binding and further restored DBS binding activity of heat-denatured p53, in vitro, in a dose-dependent manner. In vivo ELISA and immunoprecipitation analysis of NTD125-transfected cells revealed that NTD125 shifted equilibrium from p53 mutant to wild type under heat stress conditions. Further, NTD125 initiated nuclear translocation of cytoplasmic p53 in transcriptionally active state in order to activate p53 downstream genes such as p21, Bax, PUMA, Noxa and SUMO.
    Conclusion/significance: Here, we showed that a novel chaperone-like activity resides in p53-N-ter region. This study might have significance in understanding the role of p53-NTD in p53 stabilization, conformational activation and apoptosis under heat-stress conditions.
    MeSH term(s) Apoptosis ; Cell Nucleus/metabolism ; Circular Dichroism ; Cytoplasm/metabolism ; Dose-Response Relationship, Drug ; Gene Expression Regulation ; Genes, p53 ; Hot Temperature ; Humans ; Phenotype ; Proline/chemistry ; Protein Conformation ; Protein Denaturation ; Protein Structure, Tertiary ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/physiology
    Chemical Substances Tumor Suppressor Protein p53 ; Proline (9DLQ4CIU6V)
    Language English
    Publishing date 2009-10-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0007159
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