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10.1038/celldisc.2017.11 http://scihub22266oqcxt.onion/10.1038/celldisc.2017.11 C5404257!5404257 !28496990     free     free     free Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 211.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Deprecated: Implicit conversion from float 245.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Warning: imagejpeg(C:\Inetpub\vhosts\kidney.de\httpdocs\phplern\28496990 .jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117       Cell+Discov 2017 ; 3 (ä): 17011 Nephropedia Template TP {{tp|p=28496990 |t=2017. mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A |pdf=|usr=}}{{28496990 }} gab.com Text mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A JO: Cell Discov http://www.kidney.de/pget.php?&tw=1&pmid=28496990 #FOAvip Mannose-6-phosphate receptor (M6PR) that facilitates cellular uptake of M6P-bearing proteins, including serine-protease granzyme-B (Gzm-B) has an important role in T-cell activation, migration and contraction. However, molecular mechanisms controlling M6PR expression in T cells remain poorly understood. Here, we show that M6PR expression on T cells is distinctively controlled by two common ?-chain cytokines interleukin-2 (IL-2) and IL-7, and the differential M6PR expression is not caused by an altered synthesis of M6PR protein, but is a result of distinct regulation of kinesin-3 motor-protein KIF13A that transport M6PR onto cell surfaces. Using signaling pathway-specific inhibitors, we determine that IL-2 and IL-7 distinctly regulate KIF13A and ?1-adaptin and cell-surface M6PR by controlling a kinase mammalian target of rapamycin complex-1 (mTORC1). Inflammatory cytokine IL-2 and prosurvival cytokine IL-7 induce strong and weak activation of mTORC1, leading to up- and downregulation of motor-protein KIF13A and KIF13A-motorized M6PR on T cells, and formation of IL-2 and IL-7 effectors with M6PR(high) and M6PR(low) cell-surface expression, respectively. Inhibition of mTORC1 by rapamycin reduces T-cell expression of KIF13A and cell-surface M6PR, and increases T-cell survival in Listeria monocytogenes-infected mice. Using regulatory T (T(reg))-cell-enriched mouse tumor model, we determine that M6PR(high) IL-2 effectors but not M6PR(low) IL-7 effectors adoptively transferred into tumors are vulnerable to T(reg) Gzm-B-mediated cell apoptosis. Inhibition of mTORC1 or small interfering RNA-mediated knockdown of KIF13A or M6PR renders IL-2 effectors refractory to T(reg) Gzm-B lethal hit. Overall, our data offer novel mechanistic insights into T-cell M6PR regulation, and T(reg)-resistant/T(reg)-susceptible phenomenon. Furthermore, regulation of T-cell fate vis-à-vis T(reg) suppression via the mTORC1-KIF13A-M6PR axis provides a proof of concept for therapeutic strategies to target cancer, infectious and autoimmune diseases. Twit Text FOAVip mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A ????Cell Discov http://www.kidney.de/pget.php?&tw=1&pmid=28496990 #FOAvip Twit Text # Free Paper on # # # # # LINK http://www.kidney.de/pget.php?&tw=1&pmid=28496990 #FOAvip English Wikipedia <ref>{{Cite pmid|28496990 }}</ref> mTORC1 regulates mannose-6-phosphate receptor transport and T-cell vulnerability to regulatory T cells by controlling kinesin KIF13A #MMPMID28496990 Ahmed KA ; Xiang J Cell Discov 2017[]; 3 (ä): 17011 PMID28496990 show ga Mannose-6-phosphate receptor (M6PR) that facilitates cellular uptake of M6P-bearing proteins, including serine-protease granzyme-B (Gzm-B) has an important role in T-cell activation, migration and contraction. However, molecular mechanisms controlling M6PR expression in T cells remain poorly understood. Here, we show that M6PR expression on T cells is distinctively controlled by two common ?-chain cytokines interleukin-2 (IL-2) and IL-7, and the differential M6PR expression is not caused by an altered synthesis of M6PR protein, but is a result of distinct regulation of kinesin-3 motor-protein KIF13A that transport M6PR onto cell surfaces. Using signaling pathway-specific inhibitors, we determine that IL-2 and IL-7 distinctly regulate KIF13A and ?1-adaptin and cell-surface M6PR by controlling a kinase mammalian target of rapamycin complex-1 (mTORC1). Inflammatory cytokine IL-2 and prosurvival cytokine IL-7 induce strong and weak activation of mTORC1, leading to up- and downregulation of motor-protein KIF13A and KIF13A-motorized M6PR on T cells, and formation of IL-2 and IL-7 effectors with M6PR(high) and M6PR(low) cell-surface expression, respectively. Inhibition of mTORC1 by rapamycin reduces T-cell expression of KIF13A and cell-surface M6PR, and increases T-cell survival in Listeria monocytogenes-infected mice. Using regulatory T (T(reg))-cell-enriched mouse tumor model, we determine that M6PR(high) IL-2 effectors but not M6PR(low) IL-7 effectors adoptively transferred into tumors are vulnerable to T(reg) Gzm-B-mediated cell apoptosis. Inhibition of mTORC1 or small interfering RNA-mediated knockdown of KIF13A or M6PR renders IL-2 effectors refractory to T(reg) Gzm-B lethal hit. Overall, our data offer novel mechanistic insights into T-cell M6PR regulation, and T(reg)-resistant/T(reg)-susceptible phenomenon. Furthermore, regulation of T-cell fate vis-à-vis T(reg) suppression via the mTORC1-KIF13A-M6PR axis provides a proof of concept for therapeutic strategies to target cancer, infectious and autoimmune diseases. ämTORC1 regulates mannose-6-phosphate receptor transport and T-cell vul(epmc).pdf DeepDyve Pubget Overpricing