TEG-1 CD2BP2 controls miRNA levels by regulating miRISC stability in C. elegans and human cells.
MiRNAs post-transcriptionally regulate gene expression by recruiting the miRNA-induced silencing complex (miRISC) to target mRNAs. However, the mechanisms by which miRISC components are maintained at appropriate levels for proper function are largely unknown. Here, we demonstrate that Caenorhabditis elegans TEG-1 regulates the stability of two miRISC effectors, VIG-1 and ALG-1, which in turn affects the abundance of miRNAs in various families. We demonstrate that TEG-1 physically interacts with VIG-1, and complexes with mature let-7 miRNA. Also, loss of teg-1 in vivo phenocopies heterochronic defects observed in let-7 mutants, suggesting the association of TEG-1 with miRISC is necessary for let-7 to function properly during development. Loss of TEG-1 function also affects the abundance and function of other microRNAs, suggesting that TEG-1's role is not specific to let-7. We further demonstrate that the human orthologs of TEG-1, VIG-1 and ALG-1 (CD2BP2, SERBP1/PAI-RBP1 and AGO2) are found in a complex in HeLa cells, and knockdown of CD2BP2 results in reduced miRNA levels; therefore, TEG-1's role in affecting miRNA levels and function is likely conserved. Together, these data demonstrate that TEG-1 CD2BP2 stabilizes miRISC and mature miRNAs, maintaining them at levels necessary to properly regulate target gene expression.
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Chris
C
Wang
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Pratyush
P
Gupta
St-Patrick Research Group in Basic Oncology Hotel-Dieu de Quebec (Centre Hospitalier Universitaire de Quebec), Laval University Cancer Research Centre, Quebec City, Canada.
Lucile
L
Fressigne
St-Patrick Research Group in Basic Oncology Hotel-Dieu de Quebec (Centre Hospitalier Universitaire de Quebec), Laval University Cancer Research Centre, Quebec City, Canada.
Gabriel D
GD
Bossé
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Xin
X
Wang
St-Patrick Research Group in Basic Oncology Hotel-Dieu de Quebec (Centre Hospitalier Universitaire de Quebec), Laval University Cancer Research Centre, Quebec City, Canada.
Martin J
MJ
Simard
Department of Biological Sciences, University of Calgary, Calgary, Alberta, Canada.
Dave
D
Hansen
D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D060565:Argonaute Proteins / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D012323:RNA Processing, Post-Transcriptional; D000072260:RNA Splicing Factors / Q000235:genetics* / Q000378:metabolism*; D020871:RNA Stability; D018510:RNA, Helminth / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D034743:RNA-Induced Silencing Complex / Q000235:genetics* / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism
C466422:AGO2 protein, human; C558782:ALG-1 protein, C elegans; D048868:Adaptor Proteins, Signal Transducing; D060565:Argonaute Proteins; C120378:CD2BP2 protein, human; D029742:Caenorhabditis elegans Proteins; D035683:MicroRNAs; D000072260:RNA Splicing Factors; D018510:RNA, Helminth; D016601:RNA-Binding Proteins; D034743:RNA-Induced Silencing Complex; D012261:Ribonucleoproteins; C428129:SERBP1 protein, human; C573644:TEG-1 protein, C elegans; C539742:VIG-1 protein, C elegans; C474488:let-7 microRNA, C elegans