Monot Margaux, Erny Alexandra, Gineys Barbara, Desloire Sophie, Dolmazon Christine, Aublin-Gex Anne, Lotteau Vincent, Archer Fabienne, Leroux Caroline
Université de Lyon, Université Lyon 1, INRA, UMR754, Retrovirus and Comparative Pathology, UMS 3444, SFR BioSciences, Lyon, France.
CIRI U1111, UMR5308, INSERM, CNRS, Université Lyon 1, ENS de Lyon, Lyon, France.
J Virol. 2015 Aug;89(16):8462-73. doi: 10.1128/JVI.00590-15. Epub 2015 Jun 3.
Ovine pulmonary adenocarcinoma is a naturally occurring lung cancer in sheep induced by the Jaagsiekte sheep retrovirus (JSRV). Its envelope glycoprotein (Env) carries oncogenic properties, and its expression is sufficient to induce in vitro cell transformation and in vivo lung adenocarcinoma. The identification of cellular partners of the JSRV envelope remains crucial for deciphering mechanisms leading to cell transformation. We initially identified RALBP1 (RalA binding protein 1; also known as RLIP76 or RIP), a cellular protein implicated in the ras pathway, as a partner of JSRV Env by yeast two-hybrid screening and confirmed formation of RALBP1/Env complexes in mammalian cells. Expression of the RALBP1 protein was repressed in tumoral lungs and in tumor-derived alveolar type II cells. Through its inhibition using specific small interfering RNA (siRNA), we showed that RALBP1 was involved in envelope-induced cell transformation and in modulation of the mTOR (mammalian target of rapamycin)/p70S6K pathway by the retroviral envelope.
JSRV-induced lung adenocarcinoma is of importance for the sheep industry. While the envelope has been reported as the oncogenic determinant of the virus, the cellular proteins directly interacting with Env are still not known. Our report on the formation of RALBP/Env complexes and the role of this interaction in cell transformation opens up a new hypothesis for the dysregulation observed upon virus infection in sheep.
绵羊肺腺癌是由绵羊肺腺瘤逆转录病毒（JSRV）诱发的绵羊自然发生的肺癌。其包膜糖蛋白（Env）具有致癌特性，其表达足以在体外诱导细胞转化并在体内诱导肺腺癌。鉴定JSRV包膜的细胞伴侣对于解读导致细胞转化的机制仍然至关重要。我们最初通过酵母双杂交筛选鉴定出RALBP1（RalA结合蛋白1；也称为RLIP76或RIP），一种参与ras途径的细胞蛋白，作为JSRV Env的伴侣，并在哺乳动物细胞中证实了RALBP1/Env复合物的形成。RALBP1蛋白的表达在肿瘤肺组织和肿瘤来源的II型肺泡细胞中受到抑制。通过使用特异性小干扰RNA（siRNA）抑制RALBP1，我们表明RALBP1参与包膜诱导的细胞转化以及逆转录病毒包膜对mTOR（雷帕霉素哺乳动物靶标）/p70S6K途径的调节。
JSRV诱导的肺腺癌对绵羊产业具有重要意义。虽然包膜已被报道为该病毒的致癌决定因素，但与Env直接相互作用的细胞蛋白仍不清楚。我们关于RALBP/Env复合物形成及其在细胞转化中的作用的报告为绵羊病毒感染时观察到的失调现象提出了一个新的假设。
