AWD regulates timed activation of BMP signaling in intestinal stem cells to maintain tissue homeostasis

被引:21
作者
Cai, Xiaoyu Tracy [1 ]
Li, Hongjie [2 ,3 ]
Safyan, Abu [4 ,5 ,6 ]
Gawlik, Jennifer [5 ,6 ,7 ]
Pyrowolakis, George [5 ,6 ,8 ]
Jasper, Heinrich [1 ,9 ,10 ]
机构
[1] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA
[2] Stanford Univ, Dept Biol, Stanford, CA 94305 USA
[3] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA
[4] Max Planck Inst & Immunobiol & Epigenet, IMPRS MCB, D-79108 Freiburg, Germany
[5] Albert Ludwigs Univ Freiburg, Fac Biol, Inst Biol 1, D-79104 Freiburg, Germany
[6] Albert Ludwigs Univ Freiburg, Ctr Biol Syst Anal ZBSA, D-79104 Freiburg, Germany
[7] Albert Ludwigs Univ Freiburg, Spemann Grad Sch Biol & Med SGBM, D-79104 Freiburg, Germany
[8] Albert Ludwigs Univ Freiburg, Signalling Res Ctr BIOSS & CIBSS, D-79104 Freiburg, Germany
[9] Genentech Inc, Immunol Discovery, 1 DNA Way, San Francisco, CA 94080 USA
[10] Fritz Lipmann Inst, Leibniz Inst Aging, D-07745 Jena, Germany
关键词
SUPPRESSOR GENE NM23; SELF-RENEWAL; DROSOPHILA; METASTASIS; KINASE; HOMOLOG; COMPLEX; PROLIFERATION; REGENERATION; ENDOCYTOSIS;
D O I
10.1038/s41467-019-10926-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Precise control of stem cell (SC) proliferation ensures tissue homeostasis. In the Drosophila intestine, injury-induced regeneration involves initial activation of intestinal SC (ISC) proliferation and subsequent return to quiescence. These two phases of the regenerative response are controlled by differential availability of the BMP type I receptor Thickveins (Tkv), yet how its expression is dynamically regulated remains unclear. Here we show that during homeostasis, the E3 ubiquitin ligase Highwire and the ubiquitin-proteasome system maintain low Tkv protein expression. After ISC activation, Tkv is stabilized by proteasome inhibition and undergoes endocytosis due to the induction of the nucleoside diphosphate kinase Abnormal Wing Disc (AWD). Tkv internalization is required for the activation of the Smad protein Mad, and for the return to quiescence after a regenerative episode. Our data provide insight into the mechanisms ensuring tissue homeostasis by dynamic control of somatic stem cell activity.
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页数:16
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