Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling
Interleukin-11 (IL-11) receptor cleavage by the rhomboid protease RHBDL2 induces IL-11 trans-signaling
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DOI：
10.1096/fj.202002087r
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发表时间：
2021-03-01
期刊：
影响因子：
4.8
通讯作者：
Garbers, Christoph
中科院分区：
文献类型：
--
作者：
Koch, Lydia;Kespohl, Birte;Garbers, Christoph
白介素11(IL-11)是一种兼具促炎和抗炎作用的多效性细胞因子。它通过与膜结合的IL-11受体(IL-11R)结合来激活其靶细胞，然后再招募普遍表达的信号转导受体gp130的同源二聚体。除了这个经典的信号通路外，IL-11还可以与可溶性的IL-11R(sIL-11R)结合，IL-11/sIL-11R复合体通过诱导gp130同源二聚(反式信号)激活细胞。我们先前已经报道，金属蛋白酶ADAM10裂解膜结合的IL-11R，从而产生sIL-11R。在这项研究中，我们发现RHBDL2是一种迄今为止尚未被认识的替代脱落酶，可以有效地触发IL-11R的分泌。我们确定了RHBDL2使用的切割位点，它位于受体的胞外部分，靠近质膜，在Ala-370和Ser-371之间。此外，我们确定了跨膜螺旋中的关键氨基酸残基，这些氨基酸残基是IL-11R蛋白降解所必需的。我们还发现异位表达的RHBDL2能够在早期的分泌途径中切割IL-11R，而不仅仅是在质膜上，这表明它的亚细胞定位在控制其活性方面起着中心作用。此外，RHBDL2来源的sIL-11R具有生物学活性，能够执行IL-11的反式信号转导。最后，我们证明了人类突变IL-11R-A370V不会阻碍IL-11经典信号转导，但会阻止RHBDL2介导的IL-11R裂解。
Interleukin-11 (IL-11) is a pleiotropic cytokine with both pro- and anti-inflammatory properties. It activates its target cells via binding to the membrane-bound IL-11 receptor (IL-11R), which then recruits a homodimer of the ubiquitously expressed, signal-transducing receptor gp130. Besides this classic signaling pathway, IL-11 can also bind to soluble forms of the IL-11R (sIL-11R), and IL-11/sIL-11R complexes activate cells via the induction of gp130 homodimerization (trans-signaling). We have previously reported that the metalloprotease ADAM10 cleaves the membrane-bound IL-11R and thereby generates sIL-11R. In this study, we identify the rhomboid intramembrane protease RHBDL2 as a so far unrecognized alternative sheddase that can efficiently trigger IL-11R secretion. We determine the cleavage site used by RHBDL2, which is located in the extracellular part of the receptor in close proximity to the plasma membrane, between Ala-370 and Ser-371. Furthermore, we identify critical amino acid residues within the transmembrane helix that are required for IL-11R proteolysis. We also show that ectopically expressed RHBDL2 is able to cleave the IL-11R within the early secretory pathway and not only at the plasma membrane, indicating that its subcellular localization plays a central role in controlling its activity. Moreover, RHBDL2-derived sIL-11R is biologically active and able to perform IL-11 trans-signaling. Finally, we show that the human mutation IL-11R-A370V does not impede IL-11 classic signaling, but prevents RHBDL2-mediated IL-11R cleavage.