組織蛋白酶S(英文:Cathepsin S)是人類體內由CTSS基因編碼的蛋白質[6]。該基因存在利用多腺苷酸化信號的轉錄變體。[6]
Quick Facts 組織蛋白酶S, 已知的結構 ...
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組織蛋白酶S是木瓜樣蛋白酶肽酶C1家族的成員[7]。它是一種溶酶體半胱氨酸蛋白酶,可參與將抗原蛋白降解為肽以呈遞給MHC II類分子。[8][9]組織蛋白酶S可以在肺泡巨噬細胞的廣泛的pH值範圍內作為彈性蛋白酶發揮作用。[10][11]
雖然人們早已知道組織蛋白酶S在抗原呈遞中的作用[12][13],但現在更加深入地了解到組織蛋白酶S在瘙癢和疼痛或傷害感受中起地作用。[14] 傷害性活性是由組織蛋白酶S通過激活G蛋白偶聯受體家族的蛋白酶激活受體2和4作為信號分子而產生的。[15]
組織蛋白酶S由抗原呈遞細胞表達,包括巨噬細胞、B細胞、樹突狀細胞和小膠質細胞。[16][17]組織蛋白酶S也由一些上皮細胞表達。[18]在用γ-干擾素刺激後,它在人角質形成細胞中的表達有着顯着的增加,並且由於促炎性細胞因子的刺激,它在銀屑病角質形成細胞中的表達也會升高。[19]相反,皮質胸腺上皮細胞不表達組織蛋白酶S。[20][21]
雖然許多溶酶體蛋白酶最適合的pH值是酸性的[22][23][24],但組織蛋白酶S是一個例外。組織蛋白酶S在中性pH值下保持催化活性,而pH值5.0到7.5之間是組織蛋白酶S的最佳pH值範圍。[25][26]由於穩定性問題,許多溶酶體蛋白酶被困在溶酶體內。相反,組織蛋白酶S可以保持穩定並在溶酶體外具有生理作用。[27][28]包括巨噬細胞和小膠質細胞在內的免疫細胞會分泌組織蛋白酶S以響應炎症介質,包括脂多糖[29]、促炎性細胞因子[30]和中性粒細胞。[31]在體外,組織蛋白酶S在3M尿素存在下可以保留一些酶活性。[32]組織蛋白酶S作為酶原產生並通過加工被激活。[33]
組織蛋白酶S的活性受到其內源性抑制劑——胱抑素C的嚴格調節,胱抑素C在抗原呈遞中也有作用。[34][35]與胱抑素C相比,胱抑素A和胱抑素B的活性較低。[36]
組織蛋白酶S的活性切割位點 -(-Val-Val-Arg-)- 應該有至少兩個氨基酸從每一側包圍它。[37]
組織蛋白酶S在抗原呈現中起關鍵作用。MHC II類分子與小肽片段相互作用,以在抗原呈現免疫細胞表面呈遞。組織蛋白酶S參與阻止抗原加載到複合物中的恆定鏈(li chain)的降解。這種降解發生在溶酶體中。按時間順序,組織蛋白酶S的作用遵循着天冬氨酸蛋白酶進行的兩次切割。組織蛋白酶S切割Ii的殘餘片段(IiP1)並留下一小部分碎片,稱為CLIP。它與複合物有直接的聯繫。
Ii的蛋白水解很重要,因為它有助於CLIP從MHC II上解離,以便複合物得以加載選定的抗原。加載抗原後,MHC II分子移動到細胞表面。因此,我們可以推測組織蛋白酶S的過度表達可能會導致Ii的過早降解、MHC II的臨時加載和自身的免疫攻擊。相反,組織蛋白酶S的抑制將導致Ii的降解、將抗原加載到MHC II中的延遲以及在細胞表面上MHC II中未切割li的片段的不適當存在,並且它會削弱免疫反應。例如,這種MHC II不會非常有效地誘導T細胞的增殖。
在巨噬細胞中,組織蛋白酶S可以被組織蛋白酶F取代。
分泌出來的組織蛋白酶S會切割一些細胞外基質(ECM)蛋白。組織蛋白酶S被認為是已知最有效的彈性蛋白酶。組織蛋白酶S底物列表包括層粘連蛋白、纖連蛋白、彈性蛋白、骨鈣蛋白和一些膠原蛋白。它還切割基底膜的硫酸軟骨素、硫酸乙酰肝素和蛋白聚糖。組織蛋白酶S由於其彈性溶解和膠原溶解活性而在血管通透性和血管新生中發揮積極作用。例如,組織蛋白酶S對層粘連蛋白5的切割會導致促血管生成肽。組織蛋白酶S的表達可由腫瘤細胞分泌的促炎因子觸發。
在癌變中,組織蛋白酶S會促進腫瘤生長。
組織蛋白酶S的表達和活性也在銀屑病患者的皮膚中被上調。它是否在引起銀屑病具有明確的作用尚不清楚,但在同一項研究中,它被證明可以特別切割和激活銀屑病相關的促炎細胞因子IL-36γ[30]
組織蛋白酶S在傷害感受中起作用,包括瘙癢和胃腸道疼痛。組織蛋白酶S導致瘙癢和疼痛的機制與蛋白酶激活受體2和4的能力一致。[38][39]
組織蛋白酶S的合成抑制劑參與了許多針對包括類風濕性關節炎在內的免疫疾病的臨床前研究。目前,他們中至少有一個參與了銀屑病的臨床試驗。LHVS(嗎啉脲-亮氨酸-高苯丙氨酸-乙烯基碸-苯基)是研究最廣泛的組織蛋白酶S的合成抑制劑。LHVS的半抑制濃度約為5nM。 LHVS對組織蛋白酶S的抑制作用已被證明。它在創傷性腦損傷後具有神經保護作用。[40]商業抑制劑清單還包括紫斑肽(乙酰-Leu-Val-CHO)和其他抑制劑。
組織蛋白酶S已被證明是IV型星形細胞瘤(膠質母細胞瘤)患者的重要預後因素,其抑制作用顯示患者平均存活時間延長了5個月。這是因為半胱氨酸酶不能再與其他蛋白酶一起作用來分解腦細胞外基質。這樣腫瘤的擴散就停止了。科學家們宣布,這種酶可能可以預測死亡,因為它已被證明與心臟病和癌症有關。
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