A Ubiquitin-Like Protein Encoded By The "Noncoding" Rna Tincr Promotes Keratinocyte Proliferation And Wound Healing

Although long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins by definition, some lncRNAs actually contain small open reading frames that are translated. TINCR (terminal differentiation-induced ncRNA) has been recognized as a lncRNA that contributes to keratinocyte differentiation. However, we here show that TINCR encodes a ubiquitin-like protein that is well conserved among species and whose expression was confirmed by the generation of mice harboring a FLAG epitope tag sequence in the endogenous open reading frame as well as by targeted proteomics. Forced expression of this protein promoted cell cycle progression in normal human epidermal keratinocytes, and mice lacking this protein manifested a delay in skin wound healing associated with attenuated cell cycle progression in keratinocytes. We termed this protein TINCR-encoded ubiquitin-like protein (TUBL), and our results reveal a role for TINCR in the regulation of keratinocyte proliferation and skin regeneration that is dependent on TUBL.Author summary Although, by definition, long noncoding RNAs (lncRNAs) are transcripts that do not encode proteins, recent studies have shown that some lncRNAs actually contain small open reading frames (ORFs) that are translated. Although TINCR (terminal differentiation-induced ncRNA) was originally identified as a lncRNA that contributes to keratinocyte differentiation, recent mass spectrometry-based analysis has suggested that TINCR is translated. Translation of the ORF within the TINCR lncRNA was validated by generating mice that harbor an in-frame insertion of the FLAG epitope tag sequence at the COOH-terminus of the ORF. The TINCR-encoded protein contains a ubiquitin-like (Ubl) domain and was designated TUBL (TINCR-encoded ubiquitin-like protein). TUBL accelerated cell cycle progression in keratinocytes, and TUBL-deficient mice manifested delayed wound healing after injury with a biopsy punch as a result of attenuated keratinocyte proliferation. TUBL plays a key role at the protein level in the maintenance of skin homeostasis after injury through promotion of keratinocyte proliferation.