Mycobacterium tuberculosis Rv3364c reduces inflammation on LPS-induced TLR4 signaling pathway

Abstract

결핵균은 대식세포를 감염시키고 숙주세포의 선천성 면역반응을 교란시키는 다양한 결핵균 항원들을 분비하여 숙주세포 내에서 살아간다. 결핵균 항원 Rv3364c는 보존된 가상단백질로 결핵균이 대식세포에 의해 포식되면 결핵균으로부터 발현량과 분비량이 증가한다. 그러나 선천성 면역반응에서의 Rv3364c의 역할이나 염증성 질환을 조절할 수 있는 가능성에 대해서는 잘 알려져 있지 않다. 특히 톨-유사 수용체 신호전달 경로에 영향을 미치는 다양한 결핵균 항원에 대해서는 많은 연구가 진행되었지만 Rv3364c가 톨-유사 수용체 신호전달 경로에서 어떤 기능을 하는지는 알려진 바 없다. 본 연구에서는 Rv3364c가 톨-유사 수용체 4의 리간드인 LPS에 의해 유도되는 전염증성 사이토카인의 분비를 억제함을 밝혔다. Rv3364c는 내포작용 조절인자인 sorting nexin 9의 BAR 도메인과 결합함을 밝혔고, 이는 중성구 세포질 인자1으로도 알려진 p47phox와 LPS에 의해 유도되는 SNX9과의 상호작용을 억제하였다. 본 연구는 결핵균 항원인 Rv3364c가 SNX9과 결합하여 염증반응을 억제할 수 있고 이에 따라 새로운 패혈증 치료제로 사용될 기회를 제공할 것으로 사료된다.|Mycobacterium tuberculosis (M. tuberculosis) infects macrophages and survives within the host by secretes many antigens that regulate the host immune system. M. tuberculosis Rv3364c is a secretory conserved hypothetical protein and highly up-regulated and secreted from M. tuberculosis upon uptake by macrophages. However, little is known about the role of Rv3364c in inflammation signaling pathways or the possibility to control inflammatory diseases. Although much research has been conducted on the effects of various M. tuberculosis antigens on the Toll-like receptor (TLR) signaling pathway, the function of Rv3364c in the TLR signaling pathway is unknown. Here, we demonstrated that Rv3364c reduced the pro-inflammatory cytokine secretion induced by lipopolysaccharide (LPS), the ligand of TLR 4. We found that Rv3364c binds to BAR domain of sorting nexin 9 (SNX9)-regulator of endocytosis- inhibiting the interaction of SNX9 and p47phox, also known as Neutrophil cytosol factor 1, under LPS stimulation. In summary, our findings suggest that Rv3364c has anti-inflammatory properties by interacting with SNX9 and can serve as a novel anti-sepsis therapeutic strategy.; Mycobacterium tuberculosis (M. tuberculosis) infects macrophages and survives within the host by secretes many antigens that regulate the host immune system. M. tuberculosis Rv3364c is a secretory conserved hypothetical protein and highly up-regulated and secreted from M. tuberculosis upon uptake by macrophages. However, little is known about the role of Rv3364c in inflammation signaling pathways or the possibility to control inflammatory diseases. Although much research has been conducted on the effects of various M. tuberculosis antigens on the Toll-like receptor (TLR) signaling pathway, the function of Rv3364c in the TLR signaling pathway is unknown. Here, we demonstrated that Rv3364c reduced the pro-inflammatory cytokine secretion induced by lipopolysaccharide (LPS), the ligand of TLR 4. We found that Rv3364c binds to BAR domain of sorting nexin 9 (SNX9)-regulator of endocytosis- inhibiting the interaction of SNX9 and p47phox, also known as Neutrophil cytosol factor 1, under LPS stimulation. In summary, our findings suggest that Rv3364c has anti-inflammatory properties by interacting with SNX9 and can serve as a novel anti-sepsis therapeutic strategy.