SLFN11's surveillance role in protein homeostasis.

The endoplasmic reticulum (ER) is the organelle that produces functional proteins in eukaryotes. However, increased protein synthesis often causes protein misfolding, leading to ER stress and reciprocal activation of the unfolded protein response (UPR). The ubiquitinproteasome system (UPS) and ER stress-associated protein degradation (ERAD) pathways remove immature proteins. Recently, we demonstrated that Schlafen11 (SLFN11) acts as a surveillance factor for protein homeostasis by alleviating the proteotoxic stress derived from protein synthesis and maturation [1]. Schlafen (“to sleep” in German) is the name of a family of genes encompassing SLFN5, SLFN11, SLFN12, SLFN12L, SLFN13, and SLFN14 in human cells. Among the SLFN family, SLFN11 has been identified as a critical determinant for the cytotoxicity of anticancer agents targeting DNA replication across multiple cancer types. SLFN11 is recruited to damaged replication forks under replication stress. It irreversibly inhibits replication by promoting the destabilization of Cdc45-Mcm2-7-GINS (CMG) helicase complex, degrading the Chromatin Licensing and DNA Replication Factor 1 (CDT1), remodeling chromatin, and inducing immediate early genes [2, 3]. Its lack of expression in ~50% of cancer cells leads to chemoresistance. SLFN11 also plays a pivotal role inhibiting viral infection and tumorigenesis [4, 5] (Figure 1). By screening the NCATS drug library, containing 1978 compounds, we recently reported that TAK-243 (MLN7243), a first-in-class inhibitor of the ubiquitinactivating enzyme UBA1 (also known as UBE1) preferentially suppresses cell proliferation of SLFN11deficient cancer cells [1]. TAK-243 binds free ubiquitin to form irreversible ubiquitin adducts and induces ER and proteotoxic stress [6], thereby leading to cancer cell death. We also found that cancer cells that do not express SLFN11 exhibit increased global protein ubiquitylation, ER stress and UPR compared to SLFN11-proficient cells. The increased susceptibility of SLFN11-deficient cells to TAK-243 was associated with an enhanced activation of the UPR transducers PERK, phosphorylated eIF2α, phosphorylated IRE1 and ATF6. Research Perspective