A proteolytic modification of AIM promotes its renal excretion.
A proteolytic modification of AIM promotes its renal excretion.
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DOI：
10.1038/srep38762
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发表时间：
2016-12-08
影响因子：
4.6
通讯作者：
Miyazaki T
中科院分区：
文献类型：
--
作者：
Yamazaki T;Sugisawa R;Hiramoto E;Takai R;Matsumoto A;Senda Y;Nakashima K;Nelson PS;Lucas JM;Morgan A;Li Z;Yamamura KI;Arai S;Miyazaki T
巨噬细胞凋亡抑制剂（AIM，由cd5l编码）是一种多功能循环蛋白，其在多种疾病的调节中具有有益作用，其中一些通过小鼠中的AIM施用而改善。在血液中，AIM通过与IgM五聚体结合而稳定，并保持其高循环水平。调节血液AIM过度积累的机制仍然未知，尽管它很重要，因为AIM水平的组成性增加促进慢性炎症。在这里，我们发现了一个生理AIM裂解过程，诱导AIM的不稳定和尿液中的排泄。在血液中，无IgM的AIM似乎被切割，大小减小约10 kDa。切割的AIM不能与IgM结合，并被肾小球选择性过滤，从而经尿液排泄。在切割位点的氨基酸取代导致没有肾脏排泄的AIM。有趣的是，切割的AIM在促进损伤的肾脏中的死细胞碎片的清除方面保留了与全长AIM相当的效力，这是急性肾损伤恢复中的关键反应。AIM切割和由此产生的功能修饰的鉴定可能是设计用于各种疾病的安全和有效的AIM疗法的基础。
Apoptosis inhibitor of macrophage (AIM, encoded by cd5l) is a multi-functional circulating protein that has a beneficial role in the regulation of a broad range of diseases, some of which are ameliorated by AIM administration in mice. In blood, AIM is stabilized by association with IgM pentamers and maintains its high circulating levels. The mechanism regulating the excessive accumulation of blood AIM remains unknown, although it is important, since a constitutive increase in AIM levels promotes chronic inflammation. Here we found a physiological AIM-cleavage process that induces destabilization of AIM and its excretion in urine. In blood, IgM-free AIM appeared to be cleaved and reduced in size approximately 10 kDa. Cleaved AIM was unable to bind to IgM and was selectively filtered by the glomerulus, thereby excreted in urine. Amino acid substitution at the cleavage site resulted in no renal excretion of AIM. Interestingly, cleaved AIM retained a comparable potency with full-length AIM in facilitating the clearance of dead cell debris in injured kidney, which is a key response in the recovery of acute kidney injury. Identification of AIM-cleavage and resulting functional modification could be the basis for designing safe and efficient AIM therapy for various diseases.
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影响因子：
64.5
作者：
Joseph, SB;Bradley, MN;Tontonoz, P
通讯作者：
Tontonoz, P
影响因子：
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作者：
Lucas, J. M.;True, L.;Nelson, P. S.
通讯作者：
Nelson, P. S.
影响因子：
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影响因子：
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通讯作者：
Kuchroo VK
影响因子：
4.8
作者：
Ichimura, T;Bonventre, JV;Sanicola, M
通讯作者：
Sanicola, M