The Hsp40 family chaperone protein DnaJB6 enhances Schlafen1 nuclear localization which is critical for promotion of cell-cycle arrest in T-cells.
Tight control of cell-cycle progression is critical for T-lymphocytes to function properly. Slfn1 (Schlafen1) has been reported to play an important role in the establishment and maintenance of quiescence in T-lymphocytes. However, how Slfn1 accomplishes this critical function remains poorly understood. In the present study, we show that nuclear localization is a prerequisite for Slfn1 to induce cell-cycle arrest, with DnaJB6, identified as a new Slfn1-binding protein, playing a pivotal role in this process. DnaJB6, a chaperone protein of the DnaJ/Hsp (heat-shock protein) 40 family, stabilizes Slfn1 together with its partner Hsp70, and, more importantly, it enhances the nuclear import of Slfn1. Overexpression of DnaJB6 was found to increase Slfn1 nuclear accumulation and resulted in cell-cycle arrest, whereas, in DnaJB6 knock-down cells, Slfn1 was mainly sequestered in the cytoplasm and no cell-cycle arrest was observed. Furthermore, transgenic expression of DnaJB6 in T-lineage cells inhibited Slfn1's degradation, promoted its nuclear import and ultimately led to suppression of T-cell proliferation upon TCR (T-cell receptor) activation. In addition, DnaJB6 increased Slfn1's effect on its downstream target cyclin D1 in co-transfected cells. Altogether, our results demonstrate that DnaJB6 is necessary for translocation of Slfn1 into the nucleus, where Slfn1 down-regulates cyclin D1, induces cell-cycle arrest and programmes a quiescent state of T-cells.
Zhang
Yafeng
Y
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, People's Republic of China.
Yang
Zhengmin
Z
Cao
Yonghao
Y
Zhang
Shijian
S
Li
Hai
H
Huang
Ying
Y
Ding
Yu-Qiang
YQ
Liu
Xiaolong
X
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002467:Cell Nucleus / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D050956:HSP40 Heat-Shock Proteins / Q000096:biosynthesis*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018832:Molecular Chaperones / Q000096:biosynthesis*; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*
D018797:Cell Cycle Proteins; C494647:DNAJB1 protein, human; C485565:DNAJB6 protein, human; C118476:Dnajb6 protein, mouse; D050956:HSP40 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; C504818:schlafen-1 protein, mouse; D019938:Cyclin D1