Physiology and pathophysiology of a human endogenous retrovirus encoded protease that processes disease-relevant cellular proteins

大约8%的人类基因组由数百万年前外源逆转录病毒感染生殖系细胞产生的序列组成。所谓的人内源性逆转录病毒(HERV)通常由于在基因组中的长期存在而获得大量突变，不再编码以前的逆转录病毒蛋白。例外包括一种由Herv-W组编码的蛋白质，它似乎对胎盘发育至关重要，以及由所谓的Herv-K(HML-2)组的进化年轻的基因座编码的各种蛋白质。许多HERV，包括HERV-K(HML-2)，仍然在良性条件下转录，在各种疾病中以不受调控的方式转录。最近，HERV的表达被认为在各种类型的癌症和神经退行性疾病中起着重要的作用。Herv-K(HML-2)编码一种典型的处理Herv-K(HML-2)Gag蛋白的功能性蛋白酶。我们在最近的研究中发现，Herv-K(HML-2)蛋白酶也能处理大量的细胞蛋白，其中包括许多与疾病相关的蛋白。因此，Herv-K(HML-2)蛋白的表达异常伴随着与疾病相关的细胞蛋白的降解，可能与人类疾病的发生有关。在目前的研究中，我们将通过关注Herv-K(HML-2)酶的细胞生物学的特定方面和潜在的疾病相关性来进一步研究Herv-K(HML-2)酶的作用。我们的研究将为更具体地研究HERV-K(HML-2)蛋白酶处理细胞蛋白的细胞后果提供额外的重要数据。

Approximately 8% of the human genome mass consists of sequences that derive from infections of germ line cells by exogenous retroviruses millions of years ago. So-called human endogenous retroviruses (HERVs) usually acquired numerous mutations due to long-time presence in the genome and no longer encode former retroviral proteins. Exceptions include a protein encoded by the HERV-W group that appears essential for placenta development and various proteins encoded by evolutionarily young loci of the so-called HERV-K(HML-2) group. Many HERVs, including HERV-K(HML-2), are still transcribed in benign conditions and in a deregulated fashion in various diseases. A functional role of HERV expression has been suggested recently for various types of cancer and neurodegenerative diseases. HERV-K(HML-2) encodes a functional protease that typically processes HERV-K(HML-2) Gag protein. We established in our recent research that HERV-K(HML-2) protease does also process numbers of cellular proteins, among them many disease-relevant proteins. Deregulated expression of HERV-K(HML-2) protease accompanied by degradation of disease-relevant cellular proteins therefore may contribute to development of human diseases. In the current research, we will further investigate the role of HERV-K(HML-2) protease by focusing on specific aspects of the cell biology and potential disease relevance of HERV-K(HML-2) protease. Our research will generate additional important data for more specific investigations of cellular consequences of processing of cellular proteins by HERV-K(HML-2) protease.