Abstract
Human Schlafen 11 (SLFN11) is an interferon-stimulated gene (ISG) that we previously have demonstrated to ablate translation of HIV proteins based on the virus's distinct codon preference. Additionally, lack of SLFN11 expression has been linked to the resistance of cancer cells to DNA-damaging agents (DDAs). We recently resolved the underlying mechanism, finding that it involves SLFN11-mediated cleavage of select tRNAs predominantly employed in the translation of the ATR and ATM Ser/Thr kinases, thereby establishing SLFN11 as a novel tRNA endonuclease. Even though SLFN11 is thus involved in two of the most prominent diseases of our time, cancer and HIV infection, its regulation remained thus far unresolved. Using MS and bioinformatics-based approaches combined with site-directed mutagenesis, we show here that SLFN11 is phosphorylated at three different sites, which requires dephosphorylation for SLFN11 to become fully functionally active. Furthermore, we identified protein phosphatase 1 catalytic subunit γ (PPP1CC) as the upstream enzyme whose activity is required for SLFN11 to cleave tRNAs and thereby act as a selective translational inhibitor. In summary, our work has identified both the mechanism of SLFN11 activation and PPP...Continue Reading
References
Dec 10, 1998·Immunity·D A SchwarzS M Hedrick
Nov 2, 1999·The EMBO Journal·R E KiernanC Van Lint
Feb 6, 2008·Molecular and Cellular Biology·Xi TangBo Xu
May 10, 2008·Genome Biology·Jamie SniderWalid A Houry
Nov 6, 2008·Nucleic Acids Research·Patricia P Chan, Todd M Lowe
Jul 22, 2009·Gene·Olivia BustosElena de la Casa-Esperón
Apr 20, 2010·Trends in Biochemical Sciences·Mathieu BollenMonique Beullens
Apr 1, 2011·Cell Cycle·Thomas KüntzigerRandi G Syljuåsen
Mar 31, 2012·Nature·Jordi BarretinaLevi A Garraway
Aug 29, 2012·Proceedings of the National Academy of Sciences of the United States of America·Gabriele ZoppoliYves Pommier
Sep 25, 2012·Nature·Manqing LiMichael David
Feb 27, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Dennis C OteroMichael David
Oct 18, 2013·Retrovirology·Mohamed Abdel-MohsenSatish K Pillai
Dec 15, 2015·EMBO Reports·Yanhua MuJun Huang
Dec 28, 2016·PLoS Pathogens·Alex C StabellSara L Sawyer
Feb 6, 2018·Molecular Cell·Junko MuraiYves Pommier
Mar 23, 2018·Nature Communications·Jin-Yu YangSong Gao
Oct 31, 2018·Nature Structural & Molecular Biology·Manqing LiMichael David
Citations
Apr 14, 2020·Cell Biology International·Yuwen WangShi Xu
Mar 11, 2020·Virologica Sinica·Lionel Berthoux
Jan 20, 2021·Virology·Ge GuoWen-Tao Qiao
Aug 1, 2020·Blood·Yusuke OkamotoMinoru Takata
Jul 18, 2021·Nature Communications·Colin W GarvieHeidi Greulich