Cell fusion induced by ERVWE1 or measles virus causes cellular senescence

Abstract

Cellular senescence limits proliferation of potentially detrimental cells, preventing tumorigenesis and restricting tissue damage. However, the function of senescence in nonpathological conditions is unknown. We found that the human placental syncytiotrophoblast exhibited the phenotype and expressed molecular markers of cellular senescence. During embryonic development, ERVWE1-mediated cell fusion results in formation of the syncytiotrophoblast, which serves as the maternal/fetal interface at the placenta. Expression of ERVWE1 caused cell fusion in normal and cancer cells, leading to formation of hyperploid syncytia exhibiting features of cellular senescence. Infection by the measles virus, which leads to cell fusion, also induced cellular senescence in normal and cancer cells. The fused cells activated the main molecular pathways of senescence, the p53-and p16-pRbdependent pathways; the senescence-associated secretory phenotype; and immune surveillance-related proteins. Thus, fusion-induced senescence might be needed for proper syncytiotrophoblast function during embryonic development, and reuse of this senescence program later in life protects against pathological expression of endogenous fusogens and fusogenic viral infections.

Cellular senescence: from growth arrest to immunogenic conversion

“…The human NKG2D ligands primarily consist of MICA, MICB, ULBP1, ULBP2, ULBP3, ULBP4, ULBP5 and ULBP6. The transcriptional up-regulation of MICA and ULBP2 during cell senescence have been reported in senescent-activated hepatic stellate cells, replicative senescent fibroblasts and HUVECs, etoposide-induced senescent fibroblasts, fusioninduced senescent fibroblasts and chemotherapyinduced senescent multiple m yeloma cells (Krizhanovsky et al 2008;Kim et al 2008;Chuprin et al 2013;Soriani et al 2009;Lackner et al 2014). In addition to MICA and ULBP2, microarray analysis of replicative senescent fibroblasts demonstrated an increase in the expression of ULBP1 (2.75-fold) compared to growing cells, in addition to the up-regulation of HLA-E (2-fold) (Lackner et al 2014).…”

“…We define this as a shift from a passive cellular phenotype in terms of immune surveillance to one that actively promotes selfelimination by the immune system. In this model, the secretory phenotype of senescent cells serves to attract immune cells , which then recognize their target via the up-regulated ligands found on their surface (Krizhanovsky et al 2008;Kim et al 2008;Soriani et al 2009;Chuprin et al 2013). …”

“…However, the length of time within the tissue is clearly a major factor in determining whether the effect of entry into senescence will be beneficial or deleterious to the organism. The appearance of senescent cells in the short-term probably facilitates important physiological functions such as tumour suppression (Braig et al 2005;Chen et al 2005;Michaloglou et al 2005;Collado et al 2005), wound healing (Krizhanovsky et al 2008;Jun et al 2010;Fitzner et al 2012;Kim et al 2013;Demaria et al 2014) and possibly placental development (Chuprin et al 2013;Rajagopalan and Long 2012;Zhang et al 2014). However, senescent cells are known to accumulate in vivo, possibly as a result of impaired immune clearance by an ageing immune system ).…”

“…mice) do not use it at all (Smith and Kipling 2004;Itahana et al 2004). Oncogene activation (oncogene-induced senescence, OIS) (Serrano et al 1997;Zhu et al 1998), elevated reactive oxygen species (stress-induced premature senescence, SIPS) (Toussaint et al 2000) and cell-cell fusion (Chuprin et al 2013) all trigger entry into a senescent state.…”

“…Many triggers of cell senescence result in DNA damage in cells in vitro (Di Micco et al 2006;Hewitt et al 2012;Chuprin et al 2013) and in vivo (Herbig et al 2006;Wang et al 2009;Suram et al 2012). This observation gives rise to the important conceptual question of whether the DNA damage response (DDR) is an absolute requirement for immunogenic conversion.…”