Article
Developmental Biology
Shou Soeda, Masaaki Oyama, Hiroko Kozuka-Hata, Tadashi Yamamoto
Summary: Control of mRNA poly(A) tails is crucial for mRNA regulation. The CCR4-NOT complex suppresses translational activity of maternal mRNAs during oocyte maturation.
Review
Cell Biology
Lorenzo Pavanello, Michael Hall, Gerlof Sebastiaan Winkler
Summary: Accurate and precise regulation of gene expression in eukaryotes involves the coordinated control of transcription, mRNA stability, and translation. Recent progress has been made in understanding the role of sequence elements in the 3' untranslated region in mRNA degradation regulation. The recruitment of the Ccr4-Not complex to target mRNA is a critical step in mRNA decay regulation. This article reviews the role of the human Ccr4-Not complex in cytoplasmic deadenylation of mRNA, focusing on its recruitment mechanisms and general mechanisms involving the poly(A) tail.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Isioma I. I. Enwerem, Nathan D. Elrod, Chung-Te Chang, Ai Lin, Ping Ji, Jennifer A. Bohn, Yevgen Levdansky, Eric J. Wagner, Eugene Valkov, Aaron C. Goldstrohm
Summary: PUM1 and PUM2 are sequence-specific RNA-binding proteins essential for vertebrate development and neurological functions. They negatively regulate gene expression by accelerating degradation of specific mRNAs, primarily through direct interaction with the CCR4-NOT complex. These findings reveal a molecular model of repression by PUM1&2 via recruitment of CNOT deadenylation machinery in a decapping-dependent mRNA decay pathway.
Article
Biochemistry & Molecular Biology
Ying Chen, Elena Khazina, Elisa Izaurralde, Oliver Weichenrieder
Summary: CCR4 and CAF1 physically interact to form a complex that removes the 3'-poly(A) tail from cellular mRNAs, playing a central role in posttranscriptional gene expression regulation. The crystal structure of a human CCR4-CAF1 complex reveals details affecting RNA binding and hydrolysis, showing CAF1 as a tunable enzyme sensitive to pH, magnesium, and zinc ions. CAF1 is proposed as a primordial deadenylase assisted by CCR4 and NOT proteins for mRNA targeting and regulation.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biochemistry & Molecular Biology
Hannah M. Burgess, Rebecca Grande, Sofia Riccio, Ikshitaa Dinesh, Gerlof Sebastiaan Winkler, Daniel P. Depledge, Ian Mohr
Summary: Human cytomegalovirus (HCMV) extensively remodels host translatome without mRNA decay enzyme. CNOT1 and CNOT3, members of host CCR4-NOT complex, are identified as unexpected pro-viral factors that selectively regulate HCMV reproduction. Poly(A)-tails of viral mRNAs are longer and less sensitive to CCR4-NOT disruption compared to cellular mRNAs. This study reveals a new mechanism of how herpesvirus infection remodels gene expression landscape and identifies a potential therapeutic target against HCMV.
Article
Cell Biology
Zhangyuan Yin, Zhihai Zhang, Yuchen Lei, Daniel J. Klionsky
Summary: This study reveals that the Ccr4-Not complex in Saccharomyces cerevisiae has bidirectional roles in regulating autophagy before and after nutrient deprivation. Under nutrient-rich conditions, Ccr4-Not promotes the degradation of certain ATG genes to maintain basal autophagy. However, upon starvation, Ccr4-Not switches its role to promote the expression of a different subset of ATG genes, which is required for sufficient autophagy induction and activity.
Article
Biochemistry & Molecular Biology
Patrick N. Stoney, Akiko Yanagiya, Saori Nishijima, Tadashi Yamamoto
Summary: The CCR4-NOT deadenylase complex plays a crucial role in post-transcriptional regulation of gene expression in eukaryotes. CNOT7 and CNOT8, vertebrate homologs of the yeast CCR4-NOT catalytic subunit Caf1, exhibit distinct physiological functions and protein stability.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Fabian Poetz, Joshua Corbo, Yevgen Levdansky, Alexander Spiegelhalter, Doris Lindner, Vera Magg, Svetlana Lebedeva, Jorg Schweiggert, Johanna Schott, Eugene Valkov, Georg Stoecklin
Summary: The study identified RNF219 as an acetylation-regulated cofactor of the CCR4-NOT complex, which inhibits mRNA degradation mediated by the complex through interaction with NOT9. RNF219 attenuates global mRNA turnover in cells with a differential requirement of its RING domain.
NATURE COMMUNICATIONS
(2021)
Article
Biotechnology & Applied Microbiology
Sarah L. Gillen, Chiara Giacomelli, Kelly Hodge, Sara Zanivan, Martin Bushell, Ania Wilczynska
Summary: In this study, a comprehensive approach was taken to investigate post-transcriptional regulation mediated by the Ccr4-Not complex, revealing that depletion of the scaffold protein CNOT1 results in a global upregulation of mRNA stability, particularly for mRNAs enriched in G/C-ending codons. Additionally, it was found that mRNAs targeted to the ER for their translation have reduced translational efficiency when CNOT1 is depleted.
Article
Biology
Yevgen Levdansky, Tobias Raisch, Justin C. Deme, Filip Pekovic, Hans Elmlund, Susan M. Lea, Eugene Valkov
Summary: This study reveals a conserved module consisting of NOT1, NOT10, and NOT11 in the CCR4-NOT complex, and provides insights into the hierarchical assembly and stabilization of this module. Structural and biochemical characterization of human, chicken, and Drosophila ternary complexes sheds light on its evolutionary conservation.
COMMUNICATIONS BIOLOGY
(2023)
Review
Immunology
Taishin Akiyama, Tadashi Yamamoto
Summary: Lymphocyte development is precisely regulated by various mechanisms, including the CCR4-NOT complex which controls mRNA longevity by catalyzing mRNA deadenylation. This process is crucial for differentiation of lymphocytes and selection of thymocytes, as it inhibits abnormal apoptosis and induces cell quiescence.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Qionglin Zhang, Lorenzo Pavanello, Alexey Potapov, Mark Bartlam, Gerlof Sebastiaan Winkler
Summary: Regulated degradation of mature mRNA is important for gene regulation in eukaryotes. The Ccr4-Not complex, which contains Caf1 and Ccr4 subunits, is a major deadenylase involved in this process. This study used various techniques to determine the position of the nuclease domain of Ccr4, improving the model of the human Ccr4-Not nuclease module.
Article
Biochemistry & Molecular Biology
Aalam Ameerul, Hibah Almasmoum, Lorenzo Pavanello, Cyril Dominguez, Gerlof Sebastiaan Winkler
Summary: The degradation of cytoplasmic mRNA in eukaryotes involves the shortening and removal of the mRNA poly(A) tail, which is mediated by poly(A)-selective ribonuclease enzymes. In human cells, BTG2 can stimulate deadenylation of poly(A) bound by cytoplasmic poly(A)-binding protein PABPC1. This study elucidates the molecular details of the interaction between PABPC1 and BTG2 through prediction of interaction surfaces, pulldown assays, and structural modeling.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Genetics & Heredity
Fusako Munakata, Masataka Suzawa, Kumiko Ui-Tei
Summary: Human GW182 family proteins act as scaffold proteins between AGO protein and RNA silencing-related proteins, with phosphorylation of TNRC6A affecting the interaction with the CCR4-NOT complex, which may impact RNA silencing activity.
Article
Biochemistry & Molecular Biology
Shiori Fujii, Duong Long Duy, Arvin Lapiz Valderrama, Risa Takeuchi, Eri Matsuura, Ayaka Ito, Kaoru Irie, Yasuyuki Suda, Tomoaki Mizuno, Kenji Irie
Summary: This study focused on the role of deadenylases in different growth conditions and found that the Pan2-Pan3 complex, together with the Ccr4-Not complex, plays important roles in cell growth in media containing non-fermentable carbon sources. Further investigation revealed that phosphorylation of Ccr4, Pan2, and Pan3 may regulate their activities in response to changes in carbon sources.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Clyde L. Denis, Roy Richardson, Shiwha Park, Chongxu Zhang, Wen Xi, Thomas M. Laue, Xin Wang
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2018)
Article
Immunology
Fauziyya Muhammad, Anna Trivett, Dawei Wang, Darren J. Lee
EUROPEAN JOURNAL OF IMMUNOLOGY
(2019)
Article
Cell Biology
Fauziyya Y. Muhammad, Kayleigh Peters, Dawei Wang, Darren J. Lee
JOURNAL OF LEUKOCYTE BIOLOGY
(2019)
Review
Chemistry, Medicinal
Thomas M. Laue, Steven J. Shire
JOURNAL OF PHARMACEUTICAL SCIENCES
(2020)
Article
Multidisciplinary Sciences
Fauziyya Muhammad, Dawei Wang, Alyssa Montieth, Stacey Lee, Janine Preble, C. Stephen Foster, Theresa A. Larson, Kai Ding, Justin D. Dvorak, Darren J. Lee
SCIENTIFIC REPORTS
(2019)
Article
Immunology
Fauziyya Muhammad, Priscilla N. Avalos, M. H. Mursalin, Jian-Xing Ma, Michelle C. Callegan, Darren J. Lee
FRONTIERS IN IMMUNOLOGY
(2020)
Review
Immunology
Darren J. Lee
INTERNATIONAL IMMUNOPHARMACOLOGY
(2020)
Article
Immunology
Fauziyya Muhammad, Dawei Wang, Trisha McDonald, Marisa Walsh, Kayla Drenen, Alyssa Montieth, C. Stephen Foster, Darren J. Lee
JOURNAL OF AUTOIMMUNITY
(2020)
Article
Biophysics
Jennifer M. Crowther, Marita Broadhurst, Thomas M. Laue, Geoffrey B. Jameson, Alison J. Hodgkinson, Renwick C. J. Dobson
EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS
(2020)
Article
Biochemical Research Methods
Steven A. Berkowitz, Thomas Laue
Summary: Analytical ultracentrifugation (AUC) is the most widely applicable method for characterizing solution properties, with sedimentation velocity AUC (SV-AUC) being particularly important in assessing protein aggregation during drug development. The latest ultracentrifuge model, Optima, has shown evidence of sample convection due to design issues in the temperature control system, primarily affecting low rotor speeds and dilute solvent components used in AAV analysis. Diagnostic features and strategies for reducing this issue are provided.
ANALYTICAL BIOCHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Shiwha Park, Xin Wang, Wen Xi, Roy Richardson, Thomas M. Laue, Clyde L. Denis
Summary: Research shows that the non-prion form of prion-forming proteins exists in discretely sized soluble complexes and associates with molecular chaperones. This has important implications for diseases involving protein aggregation.
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS
(2022)
Article
Immunology
Trisha McDonald, Fauziyya Muhammad, Kayleigh Peters, Darren J. Lee
Summary: The study shows that MC5r and A2Ar play crucial roles in post-EAU regulatory immunity, while CD8 T cells are important in suppressing EAU, suggesting the significance of antigen presentation in autoimmune responses.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Immunology
Kayleigh Peters, Trisha Mcdonald, Fauziyya Muhammad, Marisa Walsh, Kayla Drenen, Alyssa Montieth, C. Stephen Foster, Darren J. Lee
Summary: This study reveals the mechanistic understanding of the homing requirements of different Treg populations in preventing autoimmune uveitis. It demonstrates that A2Ar-dependent Tregs migrate to the eye and secondary lymphoid tissue, expressing chemokine receptor CCR6 and CCR7. Furthermore, the study shows that CCR6 and CCR7 expression is crucial for TIGIT+ Tregs but not PD-1+ Tregs in suppressing autoimmune uveitis. Importantly, this work has clinical relevance as patients with chronic autoimmune uveitis are unable to induce the Treg populations identified in mice that home to the target tissue.
MUCOSAL IMMUNOLOGY
(2023)
Review
Pharmacology & Pharmacy
Sean Teabagy, Emma Wood, Evan Bilsbury, Sean Doherty, Priya Janardhana, Darren J. Lee
Summary: Ocular immune privilege refers to the ability of foreign tissue grafts placed in the eye to survive indefinitely. This privilege is maintained by various mechanisms, including the blood-ocular barrier, lack of lymphatics in the eye, production of immune-suppressing molecules in the ocular microenvironment, and induction of systemic regulatory immunity. Failure of ocular immune privilege can lead to uveitis, which is a group of inflammatory disorders that can cause vision loss. Current treatments for uveitis involve immunosuppressive and anti-inflammatory medications. Research on ocular immune privilege mechanisms and the development of novel uveitis treatments is ongoing.
ADVANCED DRUG DELIVERY REVIEWS
(2023)
Article
Immunology
Danlin Yang, Rachel Kroe-Barrett, Sanjaya Singh, Thomas Laue