Structural studies on the non-translational function of human asparaginyl-tRNA synthetase as a novel chemokine targeting CCR3

Abstract

Antisynthetase syndrome 은 autoimmune disease 의 하나로, aminoacyl-tRNA synthetase 에 대한 antibody 가 만들어진다. 그 중에서 asparaginyl-tRNA synthetase 에 대한 autoantibody 인 anti-KS 의 발생은 interstitial lung disease 와 밀접한 관련이 있는 것으로 보이는데 아직 생성 기전이 명확하게 밝혀지지 않았다. 본 연구에서는 human asparaginyl-tRNA synthetase 의 N 말단 부위의 결정구조를 규명하였고 그 구조가 Brugia malayi asparaginyl-tRNA synthetase 의 N 말단 부위와 유사하다는 것을 밝혔다. 또한 human asparaginyl-tRNA synthetase 의 N 말단 부위가 CC chemokine receptor 3 와 직접 결합하여 독립적으로 chemokine 활성을 가진다는 것을 보였고, 그 결합 방식을 NMR spectroscopy 기법을 이용하여 설명하였다. 나아가, interstitial lung disease 의 발달과 autoantibody 의 생성에

있어 human asparaginyl-tRNA synthetase 의 증가된 분비에 따른 비정상적인 N 말단 부위의 chemokine 활성이 잠재적 역할을 할 것이라 제시하였다.

Asparaginyl-tRNA synthetase (NRS) is not only essential in protein translation but also associated with autoimmune diseases. Particularly, patients with antibodies that recognize NRS often develop interstitial lung disease (ILD). However, the underlying mechanism of how NRS is recognized by immune cells and provokes inflammatory responses is not well-understood. Here, I found that the crystal structure of the unique N-terminal extension domain of human NRS (named as UNE-N, where -N denotes NRS) resembles that of the chemotactic N-terminal domain of NRS from a filarial nematode, Brugia malayi, which recruits and activates specific immune cells by interacting with CXC chemokine receptor 1 and 2. UNE-N induced migration of C-C chemokine receptor 3 (CCR3)-expressing cells. The chemokine activity of UNE-N was significantly reduced by suppressing CCR3 expression with CCR3-targeting siRNA, and the loop3 region of UNE-N was shown to

interact mainly with the extracellular domains of CCR3 in nuclear magnetic resonance perturbation experiments. Based on these results, evolutionarily acquired UNE-N elicits chemokine activities that would promote NRS-CCR3-mediated proinflammatory signaling in ILD.