Lysyl oxidase-like 2 processing by factor Xa modulates its activity and substrate preference.
Lysyl oxidase-like 2 processing by factor Xa modulates its activity and substrate preference.
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DOI：
10.1038/s42003-023-04748-8
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发表时间：
2023-04-07
影响因子：
5.9
通讯作者：
Santhanam, Lakshmi
中科院分区：
文献类型：
--
作者：
Wang, Huilei;Poe, Alan;Martinez Yus, Marta;Pak, Lydia;Nandakumar, Kavitha;Santhanam, Lakshmi
赖氨酸氧化酶样2 （LOXL2）已被确定为包括心血管疾病在内的几种疾病过程中细胞外基质（ECM）重塑的重要介质。因此，人们对了解LOXL2在细胞和组织中调控的机制越来越感兴趣。虽然LOXL2在细胞和组织中以全长和加工形式存在，但加工LOXL2的蛋白酶的确切身份以及加工对LOXL2功能的影响仍不完全清楚。在这里，我们发现因子Xa （FXa）是一种在Arg-338处处理LOXL2的蛋白酶。FXa加工不影响可溶性LOXL2的酶活性。然而，在血管平滑肌细胞中，FXa加工LOXL2导致ECM交联活性降低，并将LOXL2的底物偏好从IV型胶原转移到I型胶原。此外，FXa的加工增加了LOXL2和原型LOX之间的相互作用，这表明在血管ECM中有一种潜在的补偿机制来保持LOXs的总活性。FXa表达在各种器官系统中普遍存在，并且在纤维化疾病进展中与LOXL2具有相似的作用。因此，FXa对LOXL2的处理可能在LOXL2参与的病理中具有重要意义。Xa因子在LOXL2蛋白水解过程中的作用被确定，由此产生的LOXL2从胶原IV到胶原I的亲和力改变，并越来越多地与LOX结合，这表明LOX可能被招募到裂解的LOXL2沉积的区域。
Lysyl oxidase-like 2 (LOXL2) has been identified as an essential mediator of extracellular matrix (ECM) remodeling in several disease processes including cardiovascular disease. Thus, there is growing interest in understanding the mechanisms by which LOXL2 is regulated in cells and tissue. While LOXL2 occurs both in full length and processed forms in cells and tissue, the precise identity of the proteases that process LOXL2 and the consequences of processing on LOXL2’s function remain incompletely understood. Here we show that Factor Xa (FXa) is a protease that processes LOXL2 at Arg-338. Processing by FXa does not affect the enzymatic activity of soluble LOXL2. However, in situ in vascular smooth muscle cells, LOXL2 processing by FXa results in decreased cross-linking activity in the ECM and shifts substrate preference of LOXL2 from type IV collagen to type I collagen. Additionally, processing by FXa increases the interactions between LOXL2 and prototypical LOX, suggesting a potential compensatory mechanism to preserve total LOXs activity in the vascular ECM. FXa expression is prevalent in various organ systems and shares similar roles in fibrotic disease progression as LOXL2. Thus, LOXL2 processing by FXa could have significant implications in pathologies where LOXL2 is involved. A role for Factor Xa in the proteolytic processing of LOXL2 is identified and the resulting processed LOXL2 changes affinity from collagen IV to collagen I and increasingly binds to LOX, suggesting that LOX could be recruited to the regions where cleaved LOXL2 is deposited.
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