PDF(Pubmed)
Abstract：
JNK signaling is a critical regulator of inflammation and regeneration, but how it is controlled in specific tissue contexts remains unclear. Here we show that, in the Drosophila intestine, the TNF-type ligand, Eiger (Egr), is expressed exclusively by intestinal stem cells (ISCs) and enteroblasts (EBs), where it is induced by stress and during aging. Egr preferentially activates JNK signaling in a paracrine fashion in differentiated enterocytes (ECs) via its receptor, Grindelwald (Grnd). N-glycosylation genes (Alg3, Alg9) restrain this activation, and stress-induced downregulation of Alg3 and Alg9 correlates with JNK activation, suggesting a regulatory switch. JNK activity in ECs induces expression of the intermembrane protease Rhomboid (Rho), driving secretion of EGFR ligands Keren (Krn) and Spitz (Spi), which in turn activate EGFR signaling in progenitor cells (ISCs and EBs) to stimulate their growth and division, as well as to produce more Egr. This study uncovers an N-glycosylation-controlled, paracrine JNK-EGFR-JNK feedforward loop that sustains ISC proliferation during stress-induced gut regeneration.
摘要：
JNK信号是炎症和再生的关键调节因子,但它在特定组织环境中如何控制仍不清楚.在这里我们展示，在果蝇的肠道中，TNF型配体，Eiger(Egr),仅由肠干细胞（ISC）和肠母细胞（EBs）表达，它是由压力和老化引起的。Egr优先通过其受体在分化的肠细胞（EC）中以旁分泌方式激活JNK信号，格林德沃（Grnd）。N-糖基化基因（Alg3，Alg9）抑制这种激活，应激诱导的Alg3和Alg9下调与JNK激活相关，建议进行监管转换。ECs中的JNK活性诱导膜间蛋白酶菱形（Rho）的表达，驱动EGFR配体Keren（Krn）和Spitz（Spi）的分泌，从而激活祖细胞（ISC和EBs）中的EGFR信号以刺激其生长和分裂，以及生产更多的Egr。这项研究揭示了一个N-糖基化控制，旁分泌JNK-EGFR-JNK前馈环，在应激诱导的肠道再生过程中维持ISC增殖。
