A ubiquitin-like protein encoded by the “noncoding” RNA TINCR promotes keratinocyte proliferation and wound healing

Abstract

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.

pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation

“…Altogether, we are confident that our observations are mediated by the microprotein and not by the lncRNA. In agreement with our results and parallel to our work, peptides derived from pTINCR have been detected by proteomics in the human stratum corneum 77 , and another study has shown that pTINCR is associated with keratinocyte proliferation 78 . However, the molecular mechanisms behind pTINCR functions were not thoroughly explored.…”

Human skin specific long noncoding RNA HOXC13-AS regulates epidermal differentiation by interfering with Golgi-ER retrograde transport

“…Prior studies have shown that TINCR directly binds to the STAU1 protein, thus stabilizing differentiation-related mRNAs 14 . In addition to acting as a lncRNA, TINCR encodes a protein named TINCR-encoded ubiquitin-like protein (TUBL), which promotes keratinocyte proliferation and wound repair 60,61 . Further study to determine whether TINCR may play a role in keratinocyte homeostasis-to-regeneration state transition is warranted, and if TINCR is found to be involved, the determination of whether it functions as a lncRNA or TUBL in this process will be needed.…”

Re-evaluating the impact of alternative RNA splicing on proteomic diversity

“…Genome-wide translation profiling has recently revealed that small ORFs identified in lncRNA genes can code for micropeptides, polypeptides with a length of less than 100 amino acids essential for cellular growth (Chen et al, 2020). Other small peptides produced from lncRNAs have also been reported in functional studies (Odermatt et al, 1997;MacLennan and Kranias 2003;Slavoff et al, 2013;Ruiz-Orera et al, 2014;Pang, Mao, and Liu 2018;Hartford Corrine and Lal, 2020;Nita et al, 2021;Mise et al, 2022). Eukaryotic lncRNA genes are usually composed of multiple exons with an average of 2.49 exons per human lncRNA gene (Khan, Wellinger, and Laurent 2021).…”