K15 Protein of Kaposi's Sarcoma Herpesviruses Increases Endothelial Cell Proliferation and Migration through Store-Operated Calcium Entry.

Wei Chen,Liuqing Wang,Linding Wang,Bing Shen,Changqing Xu

doi:10.3390/v10060282

Wei Chen, Liuqing Wang + Show 3 more

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https://doi.org/10.3390/v10060282

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Abstract

Kaposi’s sarcoma (KS) is a tumor of the vascular endothelium that is caused by Kaposi’s sarcoma-associated herpesvirus (KSHV). K15 of KSHV is a specific gene encoding a transmembrane protein. Two highly different forms of K15, the predominant (K15P) and minor (K15M) have been identified in different KSHV strains. In genomic locations and protein topology, two K15 alleles resemble the latent membrane protein (LMP) 1 and LMP2A of Epstein–Barr virus. Both K15 proteins have motifs similar to those found in LMP1 and LMP2A. K15 therefore seems to be a hybrid of a distant evolutionary relative of LMP1 and LMP2A. Ca2+ is a second messenger and participates in numerous activities in cells, like proliferation, migration and metastasis. It has been found previously that LMP1 increased Ca2+ influx through store-operated calcium channels and blockade of LMP1 reduced store-operated Ca2+ entry (SOCE). LMP2A has similar activity. So we sought to determine whether K15 had similar activity. We showed that K15P induced Ca2+ influx and enhanced expression of Orail1, which is a vital protein in SOCE, and overexpression of K15P improved cell motility. Mutant K15P did not show these activities in HEK-293T and EA.hy 926 cells. Our results showed that K15P increased cell proliferation and migration though SOCE and established a novel mechanism for the development of KS and KSHV-associated diseases.

Highlights

Cell motility plays an important role in many diverse biological processes ranging from embryogenesis to immune responses [1]
We studied whether K15P amplified thapsigargin-stimulated store-operated Ca2+ entry (SOCE) in two cell lines
Compared with the cells infected with Lenti-K15P and vector or Lenti-K15P (YF), we obtained the same results in EA.hy926 cells (Figure 1D,F)

Summary

Introduction

Cell motility plays an important role in many diverse biological processes ranging from embryogenesis to immune responses [1]. Abnormal activation of cell motility in natural or tumor cells is the primary cause of death in the majority of cancer patients [2]. The metastatic phenotype is a complicated process, and we usually define it as the metastatic cascade. This process includes several steps: the ability to break through local physical barriers such as the basement membrane; migration from the primary tumor to blood or lymphatic vessels; survival in the circulation; and invasion of distant tissues and establishment of metastatic lesions [1,3]. Kaposi’s sarcoma (KS) is a tumor with abnormal vascular proliferation, and is one of the most frequent acquired immune deficiency syndrome (AIDS)-related cancers and a major health threat in sub-Saharan Africa [4,5]. Regarded as Viruses 2018, 10, 282; doi:10.3390/v10060282 www.mdpi.com/journal/viruses

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