The RNA-binding protein YBX1 regulates epidermal progenitors at a posttranscriptional level

Abstract

The integrity of stratified epithelia depends on the ability of progenitor cells to maintain a balance between proliferation and differentiation. While much is known about the transcriptional pathways underlying progenitor cells’ behavior in the epidermis, the role of posttranscriptional regulation by mRNA binding proteins—a rate-limiting step in sculpting the proteome—remains poorly understood. Here we report that the RNA binding protein YBX1 (Y-box binding protein-1) is a critical effector of progenitors’ function in the epidermis. YBX1 expression is restricted to the cycling keratinocyte progenitors in vivo and its genetic ablation leads to defects in the architecture of the skin. We further demonstrate that YBX1 negatively controls epidermal progenitor senescence by regulating the translation of a senescence-associated subset of cytokine mRNAs via their 3′ untranslated regions. Our study establishes YBX1 as a posttranscriptional effector required for maintenance of epidermal homeostasis.

The lncRNA MIR31HG regulates the senescence associated secretory phenotype

“…Interestingly, recent work has shown that YBX1 prevents cytokine translation in cycling keratinocytes by binding their 3'UTR. In these studies, YBX1 knock-down results in increased translation of several cytokines and therefore induction of senescence (Kwon et al, 2018). In proliferating BJ cells, knock-down of YBX1 does induce a slight decrease of cell growth consistent with this report.…”

“…Interestingly, in BRAF-induced senescence we observe that YBX1 binds a high fraction of the IL1A mRNA while binding other cytokines to a lesser extent. YBX1 binds AU-rich motifs present in the 3'UTR of cytokine mRNAs (Beiter, Hoene et al, 2015, Kwon et al, 2018, which is consistent with our IL1A 3' UTR luciferase reporter assays. However, the stronger binding of YBX1 to IL1A mRNA compared to other cytokines show some degree of speci city towards IL1A mRNA.…”

“…We observe an increase in p-YBX1 S102 in BRAF-induced senescence and, importantly, p-YBX1 S102 is reduced in the cytoplasm upon MIR31HG knock-down. Our results indicate that this post-transcriptional modi cation of YBX1 is involved in promoting IL1A translation during BRAF-induced senescence through its 3'UTR, which could explain the previously reported opposite roles of YBX1 in cytokine translation (Kwon et al, 2018). The role of p-YBX1 in translation remains to be fully understood.…”

“…YBX1 has been implicated in several cytoplasmic processes, such as translation or mRNA stability among others (Lyabin, Eliseeva et al, 2014). According to previous ndings, YBX1 prevents senescence in epidermal progenitors and knock-down of YBX1 induces senescence features in keratinocytes (Kwon, Todorova et al, 2018). Depletion of YBX1 had a minor impact on cell growth in untreated BJ ER:BRAF (Supplementary 4A and 4B).…”

“…Interestingly, treatment with the RSK inhibitor BI-D1780 failed to upregulate IL1A during senescence ( Figure 5D). YBX1 has been recently implicated in cytokine translation by binding the 3'UTR of their mRNAs (Kwon et al, 2018). Using reporter plasmids harbouring the 3'UTR of IL1A after luciferase gene we demonstrated that a WT version of YBX1 is able to increase luciferase translation in response to 4-OHT induction.…”