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  1. Article: ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes.

    Sherman, Emily J / Emmer, Brian T

    bioRxiv : the preprint server for biology

    2021  

    Abstract: The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, with ... ...

    Abstract The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, with investigation at the protein level limited by uncertain specificity of commercial ACE2 antibodies. Here, we report our development of a sensitive and specific flow cytometry-based assay for cellular ACE2 protein abundance. Application of this approach to multiple cell lines revealed an unexpected degree of cellular heterogeneity, with detectable ACE2 protein in only a subset of cells in each isogenic population. This heterogeneity was mediated at the mRNA level by transcripts predominantly initiated from the
    Language English
    Publishing date 2021-03-26
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2021.03.26.437218
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes.

    Sherman, Emily J / Emmer, Brian T

    Scientific reports

    2021  Volume 11, Issue 1, Page(s) 15900

    Abstract: The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, with ... ...

    Abstract The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, with investigation at the protein level limited by uncertain specificity of commercial ACE2 antibodies. Here, we report our development of a sensitive and specific flow cytometry-based assay for cellular ACE2 protein abundance. Application of this approach to multiple cell lines revealed an unexpected degree of cellular heterogeneity, with detectable ACE2 protein in only a subset of cells in each isogenic population. This heterogeneity was mediated at the mRNA level by transcripts predominantly initiated from the ACE2 proximal promoter. ACE2 expression was heritable but not fixed over multiple generations of daughter cells, with gradual drift toward the original heterogeneous background. RNA-seq profiling identified distinct transcriptomes of ACE2-expressing relative cells to non-expressing cells, with enrichment in functionally related genes and transcription factor target sets. Our findings provide a validated approach for the specific detection of ACE2 protein at the surface of single cells, support an epigenetic mechanism of ACE2 gene regulation, and identify specific pathways associated with ACE2 expression in HuH7 cells.
    MeSH term(s) Angiotensin-Converting Enzyme 2/analysis ; Angiotensin-Converting Enzyme 2/genetics ; COVID-19/genetics ; Cell Line ; Gene Expression ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; RNA, Messenger/genetics ; Receptors, Virus/analysis ; Receptors, Virus/genetics ; SARS-CoV-2/isolation & purification ; Transcriptome
    Chemical Substances RNA, Messenger ; Receptors, Virus ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Language English
    Publishing date 2021-08-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-021-95308-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: The small GTPase RAB10 regulates endosomal recycling of the LDL receptor and transferrin receptor in hepatocytes.

    Khan, Taslima Gani / Ginsburg, David / Emmer, Brian T

    Journal of lipid research

    2022  Volume 63, Issue 8, Page(s) 100248

    Abstract: The low-density lipoprotein receptor (LDLR) mediates the hepatic uptake of circulating low-density lipoproteins (LDLs), a process that modulates the development of atherosclerotic cardiovascular disease. We recently identified RAB10, encoding a small ... ...

    Abstract The low-density lipoprotein receptor (LDLR) mediates the hepatic uptake of circulating low-density lipoproteins (LDLs), a process that modulates the development of atherosclerotic cardiovascular disease. We recently identified RAB10, encoding a small GTPase, as a positive regulator of LDL uptake in hepatocellular carcinoma cells (HuH7) in a genome-wide CRISPR screen, though the underlying molecular mechanism for this effect was unknown. We now report that RAB10 regulates hepatocyte LDL uptake by promoting the recycling of endocytosed LDLR from RAB11-positive endosomes to the plasma membrane. We also show that RAB10 similarly promotes the recycling of the transferrin receptor, which binds the transferrin protein that mediates the transport of iron in the blood, albeit from a distinct RAB4-positive compartment. Taken together, our findings suggest a model in which RAB10 regulates LDL and transferrin uptake by promoting both slow and rapid recycling routes for their respective receptor proteins.
    MeSH term(s) Endocytosis ; Endosomes ; Hepatocytes ; Lipoproteins, LDL ; Monomeric GTP-Binding Proteins ; Receptors, LDL ; Receptors, Transferrin ; Transferrin ; rab GTP-Binding Proteins
    Chemical Substances Lipoproteins, LDL ; Receptors, LDL ; Receptors, Transferrin ; Transferrin ; Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2022-06-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1016/j.jlr.2022.100248
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Genome Editing and Hematologic Malignancy.

    Emmer, Brian T / Ginsburg, David

    Annual review of medicine

    2019  Volume 71, Page(s) 71–83

    Abstract: The modern genomic era has seen remarkable advancement in our understanding of the molecular basis for disease, yet translation of basic discoveries into new disease treatments has arguably lagged behind. Recently, breakthroughs in genome editing ... ...

    Abstract The modern genomic era has seen remarkable advancement in our understanding of the molecular basis for disease, yet translation of basic discoveries into new disease treatments has arguably lagged behind. Recently, breakthroughs in genome editing technologies have created hope for their potential to directly treat the genetic causes of disease. Like any therapeutic intervention, genome editing should be considered in light of its potential risks and benefits. In this review, we highlight the promise of genome editing therapies, as well as the conceptual and technical barriers to their clinical application, with a special emphasis on hematologic malignancies.
    MeSH term(s) CRISPR-Cas Systems/genetics ; Female ; Gene Editing/methods ; Genetic Therapy/methods ; Hematologic Neoplasms/diagnosis ; Hematologic Neoplasms/genetics ; Hematologic Neoplasms/mortality ; Hematologic Neoplasms/therapy ; Humans ; Male ; Neoplasm Invasiveness/pathology ; Neoplasm Staging ; Prognosis ; Risk Assessment ; Survival Analysis ; Treatment Outcome
    Language English
    Publishing date 2019-08-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 207930-6
    ISSN 1545-326X ; 0066-4219
    ISSN (online) 1545-326X
    ISSN 0066-4219
    DOI 10.1146/annurev-med-052318-100741
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Functional overlap between the mammalian

    Tang, Vi T / Xiang, Jie / Chen, Zhimin / McCormick, Joseph / Abbineni, Prabhodh S / Chen, Xiao-Wei / Hoenerhoff, Mark / Emmer, Brian T / Khoriaty, Rami / Lin, Jiandie D / Ginsburg, David

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by ... ...

    Abstract Proteins carrying a signal peptide and/or a transmembrane domain enter the intracellular secretory pathway at the endoplasmic reticulum (ER) and are transported to the Golgi apparatus via COPII vesicles or tubules. SAR1 initiates COPII coat assembly by recruiting other coat proteins to the ER membrane. Mammalian genomes encode two
    Language English
    Publishing date 2024-02-29
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.27.582310
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Identification of LMAN1 and SURF4 dependent secretory cargoes.

    Tang, Vi T / Abbineni, Prabhodh S / Leprevost, Felipe da Veiga / Basrur, Venkatesha / Emmer, Brian T / Nesvizhskii, Alexey I / Ginsburg, David

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted ... ...

    Abstract Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted proteins have been shown to be actively recruited into COPII vesicles/tubules by the cargo receptors LMAN1 and SURF4, the full cargo repertoire of these receptors is unknown. We now report mass spectrometry analysis of conditioned media and cell lysates from HuH7 cells CRISPR targeted to inactivate the
    Language English
    Publishing date 2023-04-06
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.06.535922
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Identification of LMAN1- and SURF4-Dependent Secretory Cargoes.

    Tang, Vi T / Abbineni, Prabhodh S / Veiga Leprevost, Felipe da / Basrur, Venkatesha / Khoriaty, Rami / Emmer, Brian T / Nesvizhskii, Alexey I / Ginsburg, David

    Journal of proteome research

    2023  Volume 22, Issue 11, Page(s) 3439–3446

    Abstract: Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted ... ...

    Abstract Most proteins secreted into the extracellular space are first recruited from the endoplasmic reticulum into coat protein complex II (COPII)-coated vesicles or tubules that facilitate their transport to the Golgi apparatus. Although several secreted proteins have been shown to be actively recruited into COPII vesicles and tubules by the cargo receptors LMAN1 and SURF4, the full cargo repertoire of these receptors is unknown. We now report mass spectrometry analysis of conditioned media and cell lysates from HuH7 cells CRISPR targeted to inactivate the
    MeSH term(s) Humans ; Carrier Proteins/metabolism ; Endoplasmic Reticulum/metabolism ; Golgi Apparatus ; Membrane Proteins/metabolism ; Protein Transport
    Chemical Substances Carrier Proteins ; Membrane Proteins ; SURF4 protein, human
    Language English
    Publishing date 2023-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078618-9
    ISSN 1535-3907 ; 1535-3893
    ISSN (online) 1535-3907
    ISSN 1535-3893
    DOI 10.1021/acs.jproteome.3c00259
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: ACE2 protein expression within isogenic cell lines is heterogeneous and associated with distinct transcriptomes

    Emily J. Sherman / Brian T. Emmer

    Scientific Reports, Vol 11, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: Abstract The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, ...

    Abstract Abstract The membrane protein angiotensin-converting enzyme 2 (ACE2) is a physiologic regulator of the renin-angiotensin system and the cellular receptor for the SARS-CoV-2 virus. Prior studies of ACE2 expression have primarily focused on mRNA abundance, with investigation at the protein level limited by uncertain specificity of commercial ACE2 antibodies. Here, we report our development of a sensitive and specific flow cytometry-based assay for cellular ACE2 protein abundance. Application of this approach to multiple cell lines revealed an unexpected degree of cellular heterogeneity, with detectable ACE2 protein in only a subset of cells in each isogenic population. This heterogeneity was mediated at the mRNA level by transcripts predominantly initiated from the ACE2 proximal promoter. ACE2 expression was heritable but not fixed over multiple generations of daughter cells, with gradual drift toward the original heterogeneous background. RNA-seq profiling identified distinct transcriptomes of ACE2-expressing relative cells to non-expressing cells, with enrichment in functionally related genes and transcription factor target sets. Our findings provide a validated approach for the specific detection of ACE2 protein at the surface of single cells, support an epigenetic mechanism of ACE2 gene regulation, and identify specific pathways associated with ACE2 expression in HuH7 cells.
    Keywords Medicine ; R ; Science ; Q
    Subject code 612
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of α1-antitrypsin.

    Zhang, Yuan / Zhu, Min / Zheng, Chunlei / Wei, Wei / Emmer, Brian T / Zhang, Bin

    The Biochemical journal

    2022  Volume 479, Issue 7, Page(s) 839–855

    Abstract: α1-antitrypsin (AAT) is a serine protease inhibitor synthesized in hepatocytes and protects the lung from damage by neutrophil elastase. AAT gene mutations result in AAT deficiency (AATD), which leads to lung and liver diseases. The AAT Z variant forms ... ...

    Abstract α1-antitrypsin (AAT) is a serine protease inhibitor synthesized in hepatocytes and protects the lung from damage by neutrophil elastase. AAT gene mutations result in AAT deficiency (AATD), which leads to lung and liver diseases. The AAT Z variant forms polymer within the endoplasmic reticulum (ER) of hepatocytes and results in reduction in AAT secretion and severe disease. Previous studies demonstrated a secretion defect of AAT in LMAN1 deficient cells, and mild decreases in AAT levels in male LMAN1 and MCFD2 deficient mice. LMAN1 is a transmembrane lectin that forms a complex with a small soluble protein MCFD2. The LMAN1-MCFD2 protein complex cycles between the ER and the Golgi. Here, we report that LMAN1 and MCFD2 knockout (KO) HepG2 and HEK293T cells display reduced AAT secretion and elevated intracellular AAT levels due to a delayed ER-to-Golgi transport of AAT. Secretion defects in KO cells were rescued by wild-type LMAN1 or MCFD2, but not by mutant proteins. Elimination of the second glycosylation site of AAT abolished LMAN1 dependent secretion. Co-immunoprecipitation experiment in MCFD2 KO cells suggested that AAT interaction with LMAN1 is independent of MCFD2. Furthermore, our results suggest that secretion of the Z variant, both monomers and polymers, is also LMAN1-dependent. Results provide direct evidence supporting that the LMAN1-MCFD2 complex is a cargo receptor for the ER-to-Golgi transport of AAT and that interactions of LMAN1 with an N-glycan of AAT is critical for this process. These results have implications in production of recombinant AAT and in developing treatments for AATD patients.
    MeSH term(s) Animals ; Calcium-Binding Proteins/metabolism ; Carrier Proteins/metabolism ; Endoplasmic Reticulum/metabolism ; Factor V/genetics ; Factor V/metabolism ; Factor VIII/genetics ; HEK293 Cells ; Humans ; Male ; Mannose-Binding Lectins/genetics ; Mannose-Binding Lectins/metabolism ; Membrane Proteins/metabolism ; Mice ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism ; alpha 1-Antitrypsin/genetics
    Chemical Substances Calcium-Binding Proteins ; Carrier Proteins ; LMAN1 protein, human ; MCFD2 protein, human ; MCFD2 protein, mouse ; Mannose-Binding Lectins ; Membrane Proteins ; Vesicular Transport Proteins ; alpha 1-Antitrypsin ; Factor V (9001-24-5) ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2022-03-24
    Publishing country England
    Document type Journal Article
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BCJ20220055
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Systemic Inflammation Gone Awry: PASH Syndrome and Temporomandibular Joint Ankylosis.

    Wargo, Jeffrey J / Emmer, Brian T

    The American journal of medicine

    2016  Volume 129, Issue 4, Page(s) e1–3

    MeSH term(s) Ankylosis/etiology ; Hidradenitis Suppurativa/complications ; Hidradenitis Suppurativa/therapy ; Humans ; Male ; Pyoderma Gangrenosum/etiology ; Pyoderma Gangrenosum/therapy ; Temporomandibular Joint Disorders/etiology ; Trismus/etiology ; Young Adult
    Language English
    Publishing date 2016-04
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 80015-6
    ISSN 1555-7162 ; 1873-2178 ; 0002-9343 ; 1548-2766
    ISSN (online) 1555-7162 ; 1873-2178
    ISSN 0002-9343 ; 1548-2766
    DOI 10.1016/j.amjmed.2015.12.019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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