A role for Caf1 in mRNA deadenylation and decay in trypanosomes and human cells

Schwede, Angela; Ellis, Louise; Luther, Julia; Carrington, Mark; Stoecklin, Georg; Clayton, Christine

doi:10.1093/nar/gkn108

Cited by 111 publications

(182 citation statements)

References 70 publications

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“…Several studies revealed a biphasic decay pattern for EP1 mRNA in bloodstream forms and identified the nucleases involved [27][28][29]46]. In one of our experiments, a decay pattern reminiscent of biphasic decay kinetics was found for GPEET mRNA in late PF (with only 0.4% GPEET-positive cells) (Fig.…”

Section: Discussionsupporting

confidence: 68%

Insights into the regulation of GPEET procyclin during differentiation from early to late procyclic forms of Trypanosoma brucei

Knüsel

Roditi

2013

Molecular and Biochemical Parasitology

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Section: Discussionsupporting

confidence: 68%

Insights into the regulation of GPEET procyclin during differentiation from early to late procyclic forms of Trypanosoma brucei

Knüsel

Roditi

2013

Molecular and Biochemical Parasitology

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“…Knockdown of CAF1 by RNA interference (RNAi) has been shown to impair the deadenylation and decay of an ARE-containing ␤-globin mRNA (25,26). In contrast, CCR4 depletion has been reported to have no effect on deadenylation of an ARE reporter mRNA (26). Mammalian cells also contain another, predominantly nuclear enzyme, poly(A) ribonuclease (PARN) (27).…”

mentioning

confidence: 99%

MAPKAP Kinase 2 Blocks Tristetraprolin-directed mRNA Decay by Inhibiting CAF1 Deadenylase Recruitment

Marchese

Aubareda

Tudor³

et al. 2010

Journal of Biological Chemistry

136

149

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Tristetraprolin (TTP) directs its target AU-rich element (ARE)-containing mRNAs for degradation by promoting removal of the poly(A) tail. The p38 MAPK pathway regulates mRNA stability via the downstream kinase MAPK-activated protein kinase 2 (MAPKAP kinase 2 or MK2), which phosphorylates and prevents the mRNA-destabilizing function of TTP. We show that deadenylation of endogenous ARE-containing tumor necrosis factor mRNA is inhibited by p38 MAPK. To investigate whether phosphorylation of TTP by MK2 regulates TTP-directed deadenylation of ARE-containing mRNAs, we used a cell-free assay that reconstitutes the mechanism in vitro. We find that phosphorylation of Ser-52 and Ser-178 of TTP by MK2 results in inhibition of TTP-directed deadenylation of ARE-containing RNA. The use of 14-3-3 protein antagonists showed that regulation of TTP-directed deadenylation by MK2 is independent of 14-3-3 binding to TTP. To investigate the mechanism whereby TTP promotes deadenylation, it was necessary to identify the deadenylases involved. The carbon catabolite repressor protein (CCR)4⅐CCR4-associated factor (CAF)1 complex was identified as the major source of deadenylase activity in HeLa cells responsible for TTP-directed deadenylation. CAF1a and CAF1b were found to interact with TTP in an RNAindependent fashion. We find that MK2 phosphorylation reduces the ability of TTP to promote deadenylation by inhibiting the recruitment of CAF1 deadenylase in a mechanism that does not involve sequestration of TTP by 14-3-3. Cyclooxygenase-2 mRNA stability is increased in CAF1-depleted cells in which it is no longer p38 MAPK/MK2-regulated.Many mammalian mRNAs contain adenosine/uridine-rich elements (AREs) 3 in their 3Ј-untranslated regions (UTRs) that target mRNAs for rapid degradation. The importance of AREs in regulation of mRNA stability has been demonstrated particularly for mRNAs of the inflammatory response. The p38 MAPK pathway inhibits ARE-mediated decay allowing for dynamic control of the expression of these mRNAs (1-3). p38 MAPK regulates mRNA stability via the downstream kinase MAPKAP kinase 2 (MK2), which phosphorylates (4, 5) and prevents the function (6, 7) of the mRNA-destabilizing ARE-binding protein, tristetraprolin (TTP). We recently showed that dual control of mRNA stability by TTP and the p38 MAPK pathway is a general mechanism, which operates for many mRNAs of the inflammatory response (8). The importance of TTP in the control of inflammatory gene expression is demonstrated by spontaneous inflammatory arthritis in TTP Ϫ/Ϫ mice arising mainly from increased tumor necrosis factor (TNF) production (9). p38 MAPK also regulates mRNA stability by direct phosphorylation and inactivation of another ARE-binding protein, KH domain-splicing regulatory protein (10, 11). p38 MAPK inhibitors fail to destabilize mRNAs of the inflammatory response in macrophages from TTP Ϫ/Ϫ mice (8, 12). Thus, it appears that in these cells, at least, TTP is entirely responsible for the effects on mRNA stability mediated by the p38 MAPK pathway.In additi...

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“…Analysis of CAF1 in Caenorhabditis elegans using RNAi and deletion alleles demonstrates that CAF1 is essential for embryonic and larval development (Molin and Puisieux, 2005). Additionally, CAF1 is required for normal growth of trypanosomes (Schwede et al, 2008). Finally, mice lacking CAF1 are sterile (Nakamura et al, 2004).…”

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confidence: 99%

Arabidopsis Deadenylases AtCAF1a and AtCAF1b Play Overlapping and Distinct Roles in Mediating Environmental Stress Responses

et al. 2009

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To maintain homeostasis in an ever-changing environment organisms have evolved mechanisms to reprogram gene expression. One central mechanism regulating gene expression is messenger RNA (mRNA) degradation, which is initiated by poly(A) tail shortening (deadenylation). The carbon catabolite repressor 4-CCR4 associated factor1 (CCR4-CAF1) complex is the major enzyme complex that catalyzes mRNA deadenylation and is conserved among eukaryotes. However, the components and functions of this global regulatory complex have not been well characterized in plants. Here we investigate the CAF1 family in Arabidopsis (Arabidopsis thaliana). We identify 11 AtCAF1 homologs and show that a subset of these genes are responsive to mechanical wounding, among them are AtCAF1a and AtCAF1b whose expression levels are rapidly and transiently induced by wounding. The differential expression profiles of the various AtCAF1s suggest that not all AtCAF1 genes are involved in stress-responsive regulation of transcript levels. Comparison of misexpressed genes identified via transcript profiling of Atcaf1a and Atcaf1b mutants at different time points before and after wounding suggests that AtCAF1a and AtCAF1b target shared and unique transcripts for deadenylation with temporal specificity. Consistent with the AtPI4Kγ3 transcript exhibiting the largest increase in abundance in Atcaf1b, AtCAF1b targets AtPI4Kγ3 mRNA for deadenylation. Stress-tolerance assays demonstrate that AtCAF1a and AtCAF1b are involved in mediating abiotic stress responses. However, AtCAF1a and AtCAF1b are not functionally redundant in all cases, nor are they essential for all environmental stresses. These findings demonstrate that these closely related proteins exhibit overlapping and distinct roles with respect to mRNA deadenylation and mediation of stress responses.

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A role for Caf1 in mRNA deadenylation and decay in trypanosomes and human cells

Cited by 111 publications

References 70 publications

Insights into the regulation of GPEET procyclin during differentiation from early to late procyclic forms of Trypanosoma brucei

Insights into the regulation of GPEET procyclin during differentiation from early to late procyclic forms of Trypanosoma brucei

MAPKAP Kinase 2 Blocks Tristetraprolin-directed mRNA Decay by Inhibiting CAF1 Deadenylase Recruitment

Arabidopsis Deadenylases AtCAF1a and AtCAF1b Play Overlapping and Distinct Roles in Mediating Environmental Stress Responses

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