Molluscum contagiosum virus (MCV) gene IMPORTANCEMCV is a human-pathogenic poxvirus that cannot be propagated in cell culture or laboratory animals. Therefore, MCV gene products have been studied predominantly in cells expressing individual viral genes. In this study, we analyzed the function of the MCV gene MC159 by expressing it from a different virus and comparing its functions to those of two well-characterized MCMV genes. In this system, MC159 displayed some but not all of the previously described functions, suggesting that the functions of a viral gene depend on the conditions under which it is expressed. Until a cell culture system for the analysis of MCV becomes available, it might be necessary to analyze MCV genes in several different systems to extrapolate their biological importance. Molluscum contagiosum virus (MCV) is a worldwide-occurring poxvirus that replicates exclusively in humans (1). Seroprevalence ranges from up to 39% in immunocompetent individuals (2, 3), affecting mostly children and young adults, to 91% in HIV-infected patients (2). Molluscum contagiosum (MC) is an infectious disease of the skin characterized by small, benign papular skin lesions that usually regress after a few months. However, in immunocompromised patients MC can become much more severe, with extensive lesions that are difficult to treat (1). This indicates the important role of the host immune system in confining and eliminating the infection.Despite its importance as a human pathogen, MCV has not been studied extensively due to technical difficulties. There is neither a cell culture system suitable for the propagation of MCV nor an animal model that recapitulates MCV replication. Therefore, individual MCV genes were studied either by using transient transfection or by expression in a recombinant vaccinia virus (VACV) as a surrogate virus (4).MCV expresses several immune-modulating proteins that are thought to contribute to the persistence of the virus (4, 5). One of these proteins, MC159, has been identified as a viral FLICE-like inhibitory protein (vFLIP) (6) due to its structural and functional similarity to cellular FLIP (cFLIP) (7). Although vFLIPs have not been found in poxviruses other than MCV, they are present in several gammaherpesviruses (6,8,9). MC159 interacts with Fasassociated protein with death domain (FADD) and procaspase-8 (formerly known as FADD-like interleukin-1␤-converting enzyme [FLICE]) and prevents Fas-and tumor necrosis factor alpha (TNF-␣)-induced apoptosis (6,(8)(9)(10). However, if caspase-8 is inhibited, receptor interacting protein kinase 1 (RIP1, RIPK1) is not cleaved and recruits RIP3 (RIPK3), initiating a pathway lead-