Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC.
Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC.
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DOI：
10.1182/bloodadvances.2021005611
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发表时间：
2022-04-26
期刊：
影响因子：
7.5
通讯作者：
Shattil SJ
中科院分区：
文献类型：
--
作者：
Kasirer-Friede A;Peuhu E;Ivaska J;Shattil SJ
血小板SHARPIN负向调节整合素α ib β3功能。血小板SHARPIN正调节炎症反应。血小板形成止血栓以防止失血，并以多种方式调节免疫和炎症。止血过程中的一个关键事件是通过β3细胞质尾部与talin和kindin -3的直接相互作用激活整合素αIIbβ3。最近，我们发现人类血小板表达连接分子Shank-associated RH domain interinteraction protein (SHARPIN)，它可以直接与αIIb细胞质尾部结合，并作为Met-1线性泛素化激活复合物（LUBAC）的成员单独促进NF-κB通路的激活。本研究通过将SHARPIN flox/flox （fl/fl）小鼠与PF4-Cre或GPIbα-Cre小鼠杂交，选择性地删除血小板中的SHARPIN，研究了SHARPIN在血小板中的作用。sharpin缺失的血小板通过α ib β3粘附于固定的纤维蛋白原上，并且通过血小板二磷酸腺苷（ADP）的反馈刺激，其扩散范围比对照组大（P < 0.01）。通过超分辨显微镜观察，sharpin缺失的血小板显示α ib β3与talin的共定位增加，可溶性纤维蛋白原的结合增加，这是对ADP亚最大浓度的反应（P < 0.05）。然而，sharpin缺失的小鼠在胶原蛋白上的血栓生长受到抑制，尾出血时间略微延长。缺乏SHARPIN的血小板在经典血小板激动剂的刺激下也表现出NF-κB活化和蛋白底物线性泛素化的降低。此外，在小鼠结肠炎和腹膜炎模型中，血小板SHARPIN的缺失导致炎症显著减少（P < 0.01）。因此，SHARPIN在血小板中发挥差异和环境依赖性作用，调节这些无核细胞的重要炎症和整合素粘附功能。
Platelet SHARPIN negatively regulates integrin αIIbβ3 function. Platelet SHARPIN positively regulates inflammatory responses. Platelets form hemostatic plugs to prevent blood loss, and they modulate immunity and inflammation in several ways. A key event during hemostasis is activation of integrin αIIbβ3 through direct interactions of the β3 cytoplasmic tail with talin and kindlin-3. Recently, we showed that human platelets express the adapter molecule Shank-associated RH domain interacting protein (SHARPIN), which can associate directly with the αIIb cytoplasmic tail and separately promote NF-κB pathway activation as a member of the Met-1 linear ubiquitination activation complex (LUBAC). Here we investigated the role of SHARPIN in platelets after crossing Sharpin flox/flox (fl/fl) mice with PF4-Cre or GPIbα-Cre mice to selectively delete SHARPIN in platelets. SHARPIN-null platelets adhered to immobilized fibrinogen through αIIbβ3, and they spread more extensively than littermate control platelets in a manner dependent on feedback stimulation by platelet adenosine diphosphate (ADP) (P < .01). SHARPIN-null platelets showed increased colocalization of αIIbβ3 with talin as assessed by super-resolution microscopy and increased binding of soluble fibrinogen in response to submaximal concentrations of ADP (P < .05). However, mice with SHARPIN-null platelets showed compromised thrombus growth on collagen and slightly prolonged tail bleeding times. Platelets lacking SHARPIN also showed reduced NF-κB activation and linear ubiquitination of protein substrates upon challenge with classic platelet agonists. Furthermore, the loss of platelet SHARPIN resulted in significant reduction in inflammation in murine models of colitis and peritonitis (P < .01). Thus, SHARPIN plays differential and context-dependent roles in platelets to regulate important inflammatory and integrin adhesive functions of these anucleate cells.
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影响因子：
6.7
作者：
Dangelmaier, C;Jin, JG;Kunapuli, SP
通讯作者：
Kunapuli, SP
影响因子：
64.8
作者：
Ikeda, Fumiyo;Deribe, Yonathan Lissanu;Skanland, Sigrid S.;Stieglitz, Benjamin;Grabbe, Caroline;Franz-Wachtel, Mirita;van Wijk, Sjoerd J. L.;Goswami, Panchali;Nagy, Vanja;Terzic, Janos;Tokunaga, Fuminori;Androulidaki, Ariadne;Nakagawa, Tomoko;Pasparakis, Manolis;Iwai, Kazuhiro;Sundberg, John P.;Schaefer, Liliana;Rittinger, Katrin;Macek, Boris;Dikic, Ivan
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Dikic, Ivan
影响因子：
37.8
作者：
Grüner, S;Prostredna, M;Nieswandt, B
通讯作者：
Nieswandt, B
影响因子：
6.4
作者：
Giles JA;Greenhalgh AD;Denes A;Nieswandt B;Coutts G;McColl BW;Allan SM
通讯作者：
Allan SM
DOI：
10.1111/febs.13547
发表时间：
2016-01
期刊：
The FEBS journal
影响因子：
--
作者：
Elliott PR;Komander D
通讯作者：
Komander D