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Article ; Online: An eIF3d-dependent switch regulates HCMV replication by remodeling the infected cell translation landscape to mimic chronic ER stress.

Thompson, Letitia / Depledge, Daniel P / Burgess, Hannah M / Mohr, Ian

2022 Volume 39, Issue 5, Page(s) 110767

Abstract: Regulated loading of eIF3-bound 40S ribosomes on capped mRNA is generally dependent upon the translation initiation factor eIF4E; however, mRNA translation often proceeds during physiological stress, such as virus infection, when eIF4E availability and ... ...

Abstract	Regulated loading of eIF3-bound 40S ribosomes on capped mRNA is generally dependent upon the translation initiation factor eIF4E; however, mRNA translation often proceeds during physiological stress, such as virus infection, when eIF4E availability and activity are limiting. It remains poorly understood how translation of virus and host mRNAs are regulated during infection stress. While initially sensitive to mTOR inhibition, which limits eIF4E-dependent translation, we show that protein synthesis in human cytomegalovirus (HCMV)-infected cells unexpectedly becomes progressively reliant upon eIF3d. Targeting eIF3d selectively inhibits HCMV replication, reduces polyribosome abundance, and interferes with expression of essential virus genes and a host gene expression signature indicative of chronic ER stress that fosters HCMV reproduction. This reveals a strategy whereby cellular eIF3d-dependent protein production is hijacked to exploit virus-induced ER stress. Moreover, it establishes how switching between eIF4E and eIF3d-responsive cap-dependent translation can differentially tune virus and host gene expression in infected cells.
MeSH term(s)	Cytomegalovirus/physiology ; Eukaryotic Initiation Factor-3/genetics ; Eukaryotic Initiation Factor-3/metabolism ; Eukaryotic Initiation Factor-4E/metabolism ; Humans ; Polyribosomes/metabolism ; Protein Biosynthesis ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Virus Replication
Chemical Substances	EIF3D protein, human ; Eukaryotic Initiation Factor-3 ; Eukaryotic Initiation Factor-4E ; RNA, Messenger
Language	English
Publishing date	2022-04-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.110767
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Article ; Online: Repression of eEF2K transcription by NF-κB tunes translation elongation to inflammation and dsDNA-sensing.

Bianco, Christopher / Thompson, Letitia / Mohr, Ian

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 45, Page(s) 22583–22590

Abstract: Gene expression is rapidly remodeled by infection and inflammation in part via transcription factor NF-κB activation and regulated protein synthesis. While protein synthesis is largely controlled by mRNA translation initiation, whether cellular ... ...

Abstract	Gene expression is rapidly remodeled by infection and inflammation in part via transcription factor NF-κB activation and regulated protein synthesis. While protein synthesis is largely controlled by mRNA translation initiation, whether cellular translation elongation factors are responsive to inflammation and infection remains poorly understood. Here, we reveal a surprising mechanism whereby NF-κB restricts phosphorylation of the critical translation elongation factor eEF2, which catalyzes the protein synthesis translocation step. Upon exposure to NF-κB-activating stimuli, including TNFα, human cytomegalovirus infection, or double-stranded DNA, eEF2 phosphorylation on Thr56, which slows elongation to limit protein synthesis, and the overall abundance of eEF2 kinase (eEF2K) are reduced. Significantly, this reflected a p65 NF-κB subunit-dependent reduction in eEF2K pre-mRNA, indicating that NF-κB activation represses eEF2K transcription to decrease eEF2K protein levels. Finally, we demonstrate that reducing eEF2K abundance regulates protein synthesis in response to a bacterial toxin that inactivates eEF2. This establishes that NF-κB activation by diverse physiological effectors controls eEF2 activity via a transcriptional repression mechanism that reduces eEF2K polypeptide abundance to preclude eEF2 phosphorylation, thereby stimulating translation elongation and protein synthesis. Moreover, it illustrates how nuclear transcription regulation shapes translation elongation factor activity and exposes how eEF2 is integrated into innate immune response networks orchestrated by NF-κB.
MeSH term(s)	Amino Acid Motifs ; DNA/genetics ; DNA/metabolism ; Elongation Factor 2 Kinase/chemistry ; Elongation Factor 2 Kinase/genetics ; Elongation Factor 2 Kinase/metabolism ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; NF-kappa B/genetics ; NF-kappa B/metabolism ; Peptide Elongation Factor 2/genetics ; Peptide Elongation Factor 2/metabolism ; Phosphorylation ; Protein Biosynthesis ; Transcription Factor RelA/genetics ; Transcription Factor RelA/metabolism
Chemical Substances	NF-kappa B ; Peptide Elongation Factor 2 ; Transcription Factor RelA ; DNA (9007-49-2) ; EEF2K protein, human (EC 2.7.1.17) ; Elongation Factor 2 Kinase (EC 2.7.11.20)
Language	English
Publishing date	2019-10-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1909143116
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Article ; Online: Basic Techniques in Drosophila Ovary Preparation.

Thompson, Letitia / Randolph, Kristen / Norvell, Amanda

Methods in molecular biology (Clifton, N.J.)

2015 Volume 1328, Page(s) 21–28

Abstract: Drosophila melanogaster oogenesis has emerged as an excellent model system to study multiple aspects of eukaryotic cell biology. Ovarian tissue can easily be isolated and analyzed through microscopy or biochemical and molecular biology techniques. Here ... ...

Abstract	Drosophila melanogaster oogenesis has emerged as an excellent model system to study multiple aspects of eukaryotic cell biology. Ovarian tissue can easily be isolated and analyzed through microscopy or biochemical and molecular biology techniques. Here we describe the isolation of ovarian tissues, techniques to enrich for egg chambers at distinct developmental stages, preparation of protein and nucleic acid extracts, and preparation for microscopic analysis of fixed tissues.
MeSH term(s)	Animals ; Drosophila melanogaster/genetics ; Drosophila melanogaster/growth & development ; Female ; Molecular Biology/methods ; Oocytes/growth & development ; Oogenesis ; Ovary
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-2851-4_2
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Article ; Online: Addressing Transportation Insecurity Among Patients With Cancer.

Graboyes, Evan M / Chaiyachati, Krisda H / Sisto Gall, Jennifer / Johnson, Wenora / Krishnan, Jerry A / McManus, Sapna S / Thompson, Letitia / Shulman, Lawrence N / Yabroff, K Robin

Journal of the National Cancer Institute

2022 Volume 114, Issue 12, Page(s) 1593–1600

Abstract: Health-care-related transportation insecurity is common in the United States. Patients with cancer are especially vulnerable because cancer care is episodic in nature, occurs over a prolonged period, is marked by frequent clinical encounters, requires ... ...

Abstract	Health-care-related transportation insecurity is common in the United States. Patients with cancer are especially vulnerable because cancer care is episodic in nature, occurs over a prolonged period, is marked by frequent clinical encounters, requires intense treatments, and results in substantial financial hardship. As a result of transportation insecurity, patients with cancer may forego, miss, delay, alter, and/or prematurely terminate necessary care. Limited data suggest that these alterations in care have the potential to increase the rates of cancer recurrence and mortality and exacerbate disparities in cancer incidence, severity, and outcomes. Transportation insecurity also negatively impacts at the informal caregiver, provider, health system, and societal levels. Recognizing that transportation is a critical determinant of outcomes for patients with cancer, there are ongoing efforts to develop evidence-based protocols to identify at-risk patients and address transportation insecurity at federal policy, health system, not-for-profit, and industry levels. In 2021, the National Cancer Policy Forum of the National Academies of Science, Engineering, and Medicine sponsored a series of webinars addressing key social determinants of health including food, housing, and transportation among patients with cancer. This commentary summarizes the formal presentations and discussions related to transportation insecurity and will 1) discuss the heterogeneous nature of transportation insecurity among patients with cancer; 2) characterize its prevalence along the cancer continuum; 3) examine its multilevel consequences; 4) discuss measurement and screening tools; 5) highlight ongoing efforts to address transportation insecurity; 6) suggest policy levers; and 7) outline a research agenda to address critical knowledge gaps.
MeSH term(s)	United States/epidemiology ; Humans ; Food Supply ; Housing ; Delivery of Health Care ; Transportation ; Government Programs ; Neoplasms/epidemiology ; Neoplasms/therapy
Language	English
Publishing date	2022-09-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2992-0
ISSN	1460-2105 ; 0027-8874 ; 0198-0157
ISSN (online)	1460-2105
ISSN	0027-8874 ; 0198-0157
DOI	10.1093/jnci/djac134
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Article ; Online: Wispy and Orb cooperate in the cytoplasmic polyadenylation of localized gurken mRNA.

Norvell, Amanda / Wong, Jason / Randolph, Kristen / Thompson, Letitia

Developmental dynamics : an official publication of the American Association of Anatomists

2015 Volume 244, Issue 10, Page(s) 1276–1285

Abstract: Background: In Drosophila, the dorsal-ventral (D-V) axis of the oocyte is dependent on Gurken (Grk) protein distribution. This is achieved through the cytoplasmic localization of grk mRNA and regulation of its translation. During mid-late stages of ... ...

Abstract	Background: In Drosophila, the dorsal-ventral (D-V) axis of the oocyte is dependent on Gurken (Grk) protein distribution. This is achieved through the cytoplasmic localization of grk mRNA and regulation of its translation. During mid-late stages of oogenesis, grk mRNA and protein are localized to the dorsal-anterior of the oocyte, while unlocalized grk transcripts are translationally silenced. As females carrying mutations in the gene encoding the CPEB protein Orb lay ventralized eggs due to insufficient Grk levels, it seemed likely that cytoplasmic polyadenylation of grk transcripts may play a role in their translational regulation. Results: We have found that grk is polyadenylated throughout oogenesis, with poly(A) tails of approximately 30-50 A residues. Hyperadenylated grk transcripts, with poly(A) tails of 50-90 As, are detected in late stage egg chambers, but they fail to accumulate in oocytes deficient in Orb or the poly(A) polymerase Wispy (Wisp). wisp females also lay weakly ventralized eggs, demonstrating that they produce inadequate amounts of Grk. Finally, unlocalized grk transcripts are also not appropriately hyperadenylated. Conclusions: Localized cytoplasmic polyadenylation of grk mRNA by Wisp and Orb is necessary to achieve appropriate Grk protein accumulation in the D/A corner of the oocyte during mid to late oogenesis.
MeSH term(s)	Animals ; Body Patterning ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Drosophila melanogaster/genetics ; Drosophila melanogaster/metabolism ; Female ; Male ; Oogenesis ; Polyadenylation ; Polynucleotide Adenylyltransferase/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Transforming Growth Factor alpha/genetics
Chemical Substances	Drosophila Proteins ; RNA-Binding Proteins ; Transforming Growth Factor alpha ; grk protein, Drosophila ; orb protein, Drosophila ; Polynucleotide Adenylyltransferase (EC 2.7.7.19) ; wisp protein, Drosophila (EC 2.7.7.19)
Language	English
Publishing date	2015-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1102541-4
ISSN	1097-0177 ; 1058-8388
ISSN (online)	1097-0177
ISSN	1058-8388
DOI	10.1002/dvdy.24311
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Ub I Zs.60: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: RNA m

Rubio, Rosa M / Depledge, Daniel P / Bianco, Christopher / Thompson, Letitia / Mohr, Ian

Genes & development

2018 Volume 32, Issue 23-24, Page(s) 1472–1484

Abstract: Modification of mRNA ... ...

Abstract	Modification of mRNA by
MeSH term(s)	AlkB Homolog 5, RNA Demethylase/genetics ; AlkB Homolog 5, RNA Demethylase/metabolism ; Animals ; Cell Line ; Cercopithecus aethiops ; Cytomegalovirus/immunology ; DNA/immunology ; Gene Expression Profiling ; Gene Expression Regulation/genetics ; Humans ; Immune System/enzymology ; Immunity, Innate/genetics ; Interferon-beta/genetics ; Interferon-beta/metabolism ; Methyltransferases/metabolism ; RNA Stability/genetics ; Vero Cells ; Virus Replication/genetics
Chemical Substances	Interferon-beta (77238-31-4) ; DNA (9007-49-2) ; AlkB Homolog 5, RNA Demethylase (EC 1.14.11.-) ; METTL14 protein, human (EC 2.1.1.-) ; Methyltransferases (EC 2.1.1.-) ; METTL3 protein, human (EC 2.1.1.62)
Language	English
Publishing date	2018-11-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.319475.118
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Zs.A 2292: 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)
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Article ; Online: Activation of mosquito immunity blocks the development of transmission-stage filarial nematodes.

Edgerton, Elizabeth B / McCrea, Abigail R / Berry, Corbett T / Kwok, Jenny Y / Thompson, Letitia K / Watson, Brittany / Fuller, Elizabeth M / Nolan, Thomas J / Lok, James B / Povelones, Michael

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 7, Page(s) 3711–3717

Abstract: Mosquito-borne helminth infections are responsible for a significant worldwide disease burden in both humans and animals. Accordingly, development of novel strategies to reduce disease transmission by targeting these pathogens in the vector are of ... ...

Abstract	Mosquito-borne helminth infections are responsible for a significant worldwide disease burden in both humans and animals. Accordingly, development of novel strategies to reduce disease transmission by targeting these pathogens in the vector are of paramount importance. We found that a strain of
MeSH term(s)	Aedes/genetics ; Aedes/immunology ; Aedes/parasitology ; Animals ; Dirofilaria immitis/growth & development ; Insect Proteins/genetics ; Insect Proteins/immunology ; Larva/growth & development ; Mosquito Vectors/genetics ; Mosquito Vectors/immunology ; Mosquito Vectors/parasitology
Chemical Substances	Insect Proteins
Language	English
Publishing date	2020-02-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1909369117
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Article ; Online: Targeting the m

Burgess, Hannah M / Depledge, Daniel P / Thompson, Letitia / Srinivas, Kalanghad Puthankalam / Grande, Rebecca C / Vink, Elizabeth I / Abebe, Jonathan S / Blackaby, Wesley P / Hendrick, Alan / Albertella, Mark R / Kouzarides, Tony / Stapleford, Kenneth A / Wilson, Angus C / Mohr, Ian

Genes & development

2021 Volume 35, Issue 13-14, Page(s) 1005–1019

Abstract: ... ...

Abstract	N
MeSH term(s)	Adenosine/analogs & derivatives ; Adenosine/genetics ; Adenosine/metabolism ; Cell Line ; Coronavirus Infections/metabolism ; Coronavirus Infections/virology ; Coronavirus OC43, Human/physiology ; Gene Expression Regulation/drug effects ; Host-Pathogen Interactions/drug effects ; Humans ; Methyltransferases/antagonists & inhibitors ; Methyltransferases/metabolism ; Nucleocapsid Proteins ; RNA Processing, Post-Transcriptional/genetics ; RNA, Viral/metabolism ; RNA-Binding Proteins/metabolism ; SARS-CoV-2/physiology ; Virus Replication/drug effects ; Virus Replication/genetics
Chemical Substances	Nucleocapsid Proteins ; RNA, Viral ; RNA-Binding Proteins ; YTHDF1 protein, human ; YTHDF3 protein, human ; N-methyladenosine (CLE6G00625) ; Methyltransferases (EC 2.1.1.-) ; METTL3 protein, human (EC 2.1.1.62) ; Adenosine (K72T3FS567)
Language	English
Publishing date	2021-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.348320.121
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Zs.A 2292: 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)
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Article: A Community Health Advisor Program to Reduce Cancer Screening Disparities in the Deep South and Appalachia: The American Cancer Society's CHA Collaborative.

Riehman, Kara S / Fisher-Borne, Marcie / Martinez, Jeremy M / Daven, Morgan / Thompson, Letitia / Fouad, Mona N / Partridge, Edward E

Health promotion practice

2017 Volume 18, Issue 5, Page(s) 734–740

Abstract: Introduction: Cancer disparities continue to exist in the United States. Community health advisors (CHAs) can play a critical role in addressing cancer disparities. The American Cancer Society (ACS) implemented a 3-year pilot CHA program in the South ... ...

Abstract	Introduction: Cancer disparities continue to exist in the United States. Community health advisors (CHAs) can play a critical role in addressing cancer disparities. The American Cancer Society (ACS) implemented a 3-year pilot CHA program in the South based on an evidence-based program to increase breast cancer screening. Study design: Evaluation assessed the extent to which ACS successfully implemented the program. Quantitative data were tracked and reported by ACS staff, and qualitative data were collected through focus groups and interviews with volunteer participants. Setting/participants: The pilot was implemented in 28 communities in nine states. ACS staff recruited volunteer community network partners (CNPs) as local advisory groups, and volunteer CHAs to conduct outreach, education, and screening navigation. Measures: Outcome measures included number of individuals educated and screened, and number of communities reaching education and screening targets. Process measures included number of volunteers recruited, number of communities reaching recruitment targets, and implementation process, challenges, and successes. Results: A total of 383 CHAs were recruited and recruitment goals were met in 68%; 31,439 individuals were educated, and 93% of communities reached education goals. In all, 5,056 individuals were screened, but screening goals were attained in only 36% of communities. Conclusion: This pilot demonstrates the ability of ACS to adapt and disseminate an evidence-based program to fit into its volunteer-based outreach model. ACS built community network partnerships, recruited a cadre of volunteers, and trained them to conduct education and screening navigation.
MeSH term(s)	American Cancer Society/organization & administration ; Appalachian Region ; Community Health Workers/organization & administration ; Early Detection of Cancer/utilization ; Female ; Health Promotion/organization & administration ; Humans ; Male ; Organizational Objectives ; Pilot Projects ; Public Health ; Qualitative Research ; Southeastern United States ; United States ; Volunteers
Language	English
Publishing date	2017-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2036801-X
ISSN	1552-6372 ; 1524-8399
ISSN (online)	1552-6372
ISSN	1524-8399
DOI	10.1177/1524839917696712
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