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

Nita, Akihiro; Matsumoto, Akinobu; Tang, Ronghao; Shiraishi, Chisa; Ichihara, Kazuya; Saito, Daisuke; Suyama, Mikita; Yasuda, Tomoharu; Tsuji, Gaku; Furue, Masutaka; Katayama, Bunpei; Ozawa, Toshiyuki; Murata, Takaho; Dainichi, Teruki; Kabashima, Kenji; Hatano, Atsushi; Matsumoto, Masaki; Nakayama, Keiichi I.

doi:10.1371/journal.pgen.1009686

Cited by 17 publications

(20 citation statements)

References 37 publications

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“…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.…”

Section: Discussionsupporting

confidence: 93%

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

et al. 2022

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The human transcriptome contains thousands of small open reading frames (sORFs) that encode microproteins whose functions remain largely unexplored. Here, we show that TINCR lncRNA encodes pTINCR, an evolutionary conserved ubiquitin-like protein (UBL) expressed in many epithelia and upregulated upon differentiation and under cellular stress. By gain- and loss-of-function studies, we demonstrate that pTINCR is a key inducer of epithelial differentiation in vitro and in vivo. Interestingly, low expression of TINCR associates with worse prognosis in several epithelial cancers, and pTINCR overexpression reduces malignancy in patient-derived xenografts. At the molecular level, pTINCR binds to SUMO through its SUMO interacting motif (SIM) and to CDC42, a Rho-GTPase critical for actin cytoskeleton remodeling and epithelial differentiation. Moreover, pTINCR increases CDC42 SUMOylation and promotes its activation, triggering a pro-differentiation cascade. Our findings suggest that the microproteome is a source of new regulators of cell identity relevant for cancer.

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Section: Discussionsupporting

confidence: 93%

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

et al. 2022

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Piipponen

Liu

et al. 2022

Preprint

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After a skin injury, keratinocytes switch from a state of homeostasis to one of regeneration leading to the reconstruction of the epidermal barrier. The regulatory mechanism of gene expression underpinning this key switch during human skin wound healing is enigmatic. Long noncoding RNAs (lncRNAs) constitute a new horizon in the understanding of the regulatory programmes encoded in the mammalian genome. By comparing the transcriptome of an acute human wound and skin from the same donor as well as keratinocytes isolated from these paired tissue samples, we generated a list of lncRNAs showing changed expression in keratinocytes during wound repair. Our study focused on HOXC13-AS, a recently evolved human lncRNA specifically expressed in epidermal keratinocytes, and we found that its expression was temporally downregulated during wound healing. In line with its enrichment in suprabasal keratinocytes, HOXC13-AS was found to be increasingly expressed during keratinocyte differentiation, but its expression was reduced by EGFR signalling. After HOXC13-AS knockdown or overexpression in human primary keratinocytes undergoing differentiation induced by cell suspension or calcium treatment and in organotypic epidermis, we found that keratinocyte differentiation was promoted, while the cell inflammatory response was suppressed. Moreover, RNA pull-down assays followed by mass spectrometry and RNA immunoprecipitation analysis revealed that mechanistically HOXC13-AS sequestered the coat complex subunit alpha (COPA) protein and interfered with Golgi-to-endoplasmic reticulum (ER) molecular transport, resulting in ER stress and enhanced keratinocyte differentiation. In summary, we identified HOXC13-AS as a crucial regulator of human epidermal differentiation.

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“…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).…”

Section: Contribution Of Long Non-coding Rnas and Circular Rnasmentioning

confidence: 99%

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

et al. 2023

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Alternative splicing (AS) constitutes a mechanism by which protein-coding genes and long non-coding RNA (lncRNA) genes produce more than a single mature transcript. From plants to humans, AS is a powerful process that increases transcriptome complexity. Importantly, splice variants produced from AS can potentially encode for distinct protein isoforms which can lose or gain specific domains and, hence, differ in their functional properties. Advances in proteomics have shown that the proteome is indeed diverse due to the presence of numerous protein isoforms. For the past decades, with the help of advanced high-throughput technologies, numerous alternatively spliced transcripts have been identified. However, the low detection rate of protein isoforms in proteomic studies raised debatable questions on whether AS contributes to proteomic diversity and on how many AS events are really functional. We propose here to assess and discuss the impact of AS on proteomic complexity in the light of the technological progress, updated genome annotation, and current scientific knowledge.

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

Cited by 17 publications

References 37 publications

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

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

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

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

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