Modulation of T cell development and activation by novel members of the Schlafen (slfn) gene family harbouring an RNA helicase-like motif

Abstract

The regulatory networks governing development and differentiation of hematopoietic cells are incompletely understood. Members of the Schlafen (Slfn) protein family have been implicated in the regulation of cell growth and T cell development. We have identified and chromosomally mapped four new members, slfn5, slfn8, slfn9 and slfn10, which belong to a distinct subgroup within this gene family. The characteristic feature of these proteins is the presence of sequence motifs identifying them as distinct members of the superfamily I of DNA/RNA helicases. A significant role of these newly identified members in hematopoietic cell differentiation is suggested based on their differential regulation (i) in developing and activated T cells, (ii) in LPS or IFNgamma activated macrophages, (iii) upon IL6 or LIF driven terminal differentiation of myeloblastic M1 cells into macrophage-like cells, and (iv) in splenocytes of mice infected with Listeria monocytogenes. In contrast to wild-type cells, IRF-1 and IFNalpha/betaR deficient macrophages, although undergoing growth arrest, fail to upregulate slfn gene expression upon IFNgamma or LPS stimulation, respectively. Therefore, an essential participation in IFNgamma or LPS induced growth arrest appears unlikely. Likewise, ectopic expression of the newly identified slfn family members in fibroblasts did not reveal a general impact on growth control. In contrast, transgenic T-cell specific expression of a representative member of this new subfamily, slfn8, resulted in profoundly impaired T cell development and peripheral T cells showed a reduced proliferative potential. Thus, functional participation of slfn8 in the regulatory networks governing T cell development and growth appears to be cell type specific.

Combination of host susceptibility and Mycobacterium tuberculosis virulence define gene expression profile in the host

“…Members of the Schlafen (Slfn) gene family are involved in T-cell activation and activation of Mf or myeloid cell differentiation [30]. All of the Schlafen genes detected in our study were also differentially regulated during rheumatoid arthritis [31].…”

Expression and Regulatory Effects of Murine Schlafen (Slfn) Genes in Malignant Melanoma and Renal Cell Carcinoma

“…Notably, our previous studies have shown that in the human system, only SLFN5 is up-regulated by type I IFNs in malignant melanoma cells and that its inducible expression correlates with IFN responses (18). Human SLFN5 contains an RNA/DNA helicase motif, as well as a nuclear localization signal, which is not seen in group I Slfns but only in group III Slfns in the mouse system (3,25). Although mouse Slfn5 is not a functional homologue of human SLFN5, the fact that murine Slfn5 does not appear to play a key role in the control of proliferation of mouse malignant melanoma cells, further underscores the functional diversity and differences of function between murine versus human SLFN isoforms.…”

“…Slfn1 and -2 belong to group I or short Slfns; Slfn3 and -4 belong to group II or intermediate Slfns; and Slfn5, -8, -9, and -14 to group III or long Slfns (2, 3). All Slfns share a specific slfn box domain, localized adjacent to an AAA domain (3,4). Groups II and III Slfns share an additional Slfn-specific domain defined by the sequence SerTrp-Ala-Asp-Leu, called the SWADL domain (3,4).…”

“…All Slfns share a specific slfn box domain, localized adjacent to an AAA domain (3,4). Groups II and III Slfns share an additional Slfn-specific domain defined by the sequence SerTrp-Ala-Asp-Leu, called the SWADL domain (3,4). Finally, members of group III exhibit a C-terminal extension containing motif, homologous to the superfamily I of DNA/RNA helicases (5-7).…”

Differential DNA methylation and PM2.5 species in a 450K epigenome-wide association study

“…42,43 SLFN11, a member of the SLFN family, potently and specifically abrogates the production of retroviruses, e.g., human immunodeficiency virus (HIV-1). 33 Using cells with endogenously high and low SLFN11 expression and siRNA-mediated silencing, Zoppoli et al 44 found that SLFN11 causally determines cell death and cell cycle arrest in response to DNA-damaging agents in cancer cells from different tissues of origin.…”