Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation
Yaoyao Zou, … , Song Guo Zheng, Hanshi Xu
Yaoyao Zou, … , Song Guo Zheng, Hanshi Xu
Published September 10, 2018
Citation Information: J Clin Invest. 2018;128(10):4510-4524. https://doi.org/10.1172/JCI97965.
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Research Article Immunology

Long noncoding RNA LERFS negatively regulates rheumatoid synovial aggression and proliferation

Abstract

Fibroblast-like synoviocytes (FLSs) are critical to synovial aggression and joint destruction in rheumatoid arthritis (RA). The role of long noncoding RNAs (lncRNAs) in RA is largely unknown. Here, we identified a lncRNA, LERFS (lowly expressed in rheumatoid fibroblast-like synoviocytes), that negatively regulates the migration, invasion, and proliferation of FLSs through interaction with heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Under healthy conditions, by binding to the mRNA of RhoA, Rac1, and CDC42 — the small GTPase proteins that control the motility and proliferation of FLSs — the LERFS–hnRNP Q complex decreased the stability or translation of target mRNAs and downregulated their protein levels. But in RA FLSs, decreased LERFS levels induced a reduction of the LERFS–hnRNP Q complex, which reduced the binding of hnRNP Q to target mRNA and therefore increased the stability or translation of target mRNA. These findings suggest that a decrease in synovial LERFS may contribute to synovial aggression and joint destruction in RA and that targeting the lncRNA LERFS may have therapeutic potential in patients with RA.

Authors

Yaoyao Zou, Siqi Xu, Youjun Xiao, Qian Qiu, Maohua Shi, Jingnan Wang, Liuqin Liang, Zhongping Zhan, Xiuyan Yang, Nancy Olsen, Song Guo Zheng, Hanshi Xu

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Figure 5

LERFS–hnRNP Q complex coregulates the expression of RhoA, Rac1, and CDC42.

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LERFS–hnRNP Q complex coregulates the expression of RhoA, Rac1, and CDC4...
(A and B) Effect of LERFS overexpression on mRNA (A) and protein (B) expression of RhoA, Rac1, and CDC42 in RA FLSs. (C) Effect of LERFS overexpression on the activation of RhoA, Rac1, and CDC42. RhoA, Rac1, and CDC42 activity was measured by G-LISA. (D–F) Effect of hnRNP Q knockdown on expression levels of mRNA (D) and protein (E) and activity (F) of RhoA, Rac1, and CDC42. (G) Effect of LERFS overexpression on protein expression of hnRNP Q. (A–G) *P < 0.05, **P < 0.01, and ***P < 0.001 versus vector or siC, by Student’s t test. (H) RIP detection of the combination of hnRNP Q and target mRNAs in RA FLSs. Values were normalized to the input. ***P < 0.001 versus IgG, by Student’s t test. (I) Effect of LERFS overexpression on the association between hnRNP Q and mRNA expression of RhoA, Rac1, and CDC42. Cell lysates from RA FLSs infected with control lentivirus (Vector) or LERFS OE were measured by RIP assay using antibodies against hnRNP Q or control IgG, followed by RT-qPCR assay of the indicated targets. Values were normalized to the input. *P < 0.05 versus vector, by Student’s t test. (J and K) Effect of hnRNP Q knockdown on LERFS overexpression–induced protein expression and activation of RhoA, Rac1, and CDC42. RA FLSs were transfected with hnRNP Q siRNA or siC for 24 hours, followed by infection of control lentivirus or LERFS OE. Three days later, cells were collected and subjected to Western blot analysis and G-LISA. Data shown are the quantification of protein levels (J) and activity (K) of RhoA, Rac1, and CDC42. Data are expressed as the mean ± SEM of 5 independent experiments involving 5 different RA patients. *P < 0.05 and ***P < 0.001, versus siC plus vector; #P < 0.05 and ##P < 0.01, versus siC plus LERFS OE, by 1-way ANOVA.