DDX6 Orchestrates Mammalian Progenitor Function through the mRNA Degradation and Translation Pathways

• Published in: Molecular cell Vol. 60; no. 1; pp. 118 - 130
• Main Authors: Wang, Ying, Arribas-Layton, Marc, Chen, Yifang, Lykke-Andersen, Jens, Sen, George L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2015
• Subjects: Cell Self Renewal; Cells, Cultured; DEAD-box RNA Helicases - metabolism; Epidermis - physiology; Eukaryotic Initiation Factor-4E - metabolism; Humans; Kruppel-Like Transcription Factors - genetics; Polyribosomes - metabolism; Protein Biosynthesis; Proto-Oncogene Proteins - metabolism; RNA Folding; RNA Stability; RNA, Messenger - chemistry; RNA, Messenger - metabolism; Stem Cells - metabolism; Y-Box-Binding Protein 1 - metabolism
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.08.014

In adult tissues, stem and progenitor cells must balance proliferation and differentiation to maintain homeostasis. How this is done is unclear. Here, we show that the DEAD box RNA helicase, DDX6 is necessary for maintaining adult progenitor cell function. DDX6 loss results in premature differentiation and decreased proliferation of epidermal progenitor cells. To maintain self-renewal, DDX6 associates with YBX1 to bind the stem loops found in the 3′ UTRs of regulators of proliferation/self-renewal (CDK1, EZH2) and recruit them to EIF4E to facilitate their translation. To prevent premature differentiation of progenitor cells, DDX6 regulates the 5′ UTR of differentiation inducing transcription factor, KLF4 and degrades its transcripts through association with mRNA degradation proteins. Our results demonstrate that progenitor function is maintained by DDX6 complexes through two distinct pathways that include the degradation of differentiation-inducing transcripts and by promoting the translation of self-renewal and proliferation mRNAs.
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•DDX6 is necessary for epidermal progenitor cell function•YBX1 recruits DDX6 and EIF4E to self-renewal mRNAs to promote their translation•DDX6 binds stem-loop structures in the 3′ UTRs of mRNAs to promote polysome loading•DDX6 associates with EDC3 to destabilize KLF4 mRNA to prevent differentiation
It is currently unclear how progenitor cells sustain the expression of self-renewal and proliferation genes while keeping differentiation-promoting mRNAs at low levels. Here Wang et al. demonstrate that the complex of DDX6/YBX1/EIF4E promotes the translation of self-renewal/proliferation transcripts whereas DDX6/EDC3 degrades differentiation-inducing mRNAs to maintain epidermal self-renewal.