Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt.
Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt.
复制标题
人类巨细胞病毒糖蛋白引发的信号传导介导 Akt 的异常激活。
DOI：
10.1128/jvi.00167-20
复制
发表时间：
2020
影响因子：
5.4
通讯作者：
Chan,GaryC
中科院分区：
文献类型：
--
作者：
Mahmud,Jamil;Miller,MichaelJ;Altman,AaronM;Chan,GaryC
人巨细胞病毒（HCMV）是免疫功能低下和免疫无效个体发病和死亡的主要原因。HCMV诱导的信号传导在病毒进入期间启动，刺激Akt的快速非经典激活，以驱动短寿命单核细胞分化为长寿命巨噬细胞，这对于病毒传播和持久性至关重要。我们发现HCMV糖蛋白gB和gH分别直接结合并激活细胞表皮生长因子受体（EGFR）和整合素β1，以重塑单核细胞内的经典Akt信号传导。Akt信号网络的重塑是由于非传统Akt激活剂被募集到gB或gH产生的受体信号复合物中。尽管p110δ是单核细胞内发现的主要PI 3 K亚型，但由p110β催化亚基组成的磷酸肌醇3-激酶（PI 3 K）仍被募集到gB/EGFR复合物中。同时，含有SH 2结构域的肌醇5-磷酸酶1（SHIP 1）被募集到gH/整联蛋白β1复合物中，这对异常Akt激活至关重要，因为SHIP 1将PI 3 K信号传导转向非经典途径。尽管整合素β1是SHIP 1募集所必需的，但gB激活的EGFR介导SHIP 1激活，强调了gB和gH介导的信号传导之间的相互作用对HCMV感染期间Akt独特激活的重要性。事实上，SHIP 1激活介导Mcl-1和HSP 27的表达增加，这两种Akt依赖性抗凋亡蛋白在HCMV感染期间特异性上调，但在生长因子治疗期间不上调。总的来说，我们的数据表明，HCMV糖蛋白gB和gH的工作在演唱会上启动HCMV特异性信号体负责Akt的非典型激活所需的感染的单核细胞的生存和最终的病毒persistence.IMPORTANCEHuman巨细胞病毒（HCMV）感染是世界各地流行的，无论社会经济条件和地理位置的血清阳性率达到100%，在一些发展中国家。虽然在健康个体中无症状，但HCMV可在免疫功能低下或免疫无效的患者中引起严重的多器官疾病。HCMV疾病是感染后单核细胞介导的病毒系统性传播的直接后果。由于单核细胞是短寿命细胞，HCMV必须通过诱导Akt（一种丝氨酸/苏氨酸蛋白激酶）的明显激活来破坏这些血细胞的自然短寿命。在这项工作中，我们证明了HCMV糖蛋白gB和gH串联工作，重新路由经典的宿主细胞受体信号传导异常激活Akt和驱动受感染的单核细胞的存活。破译HCMV如何调节细胞途径以诱导单核细胞存活对于开发一类新的抗HCMV药物非常重要，这些药物可以通过消除受感染的单核细胞来靶向和预防病毒的传播。
Human cytomegalovirus (HCMV) is a major cause of morbidity and mortality among immunocompromised and immunonaive individuals. HCMV-induced signaling initiated during viral entry stimulates a rapid noncanonical activation of Akt to drive the differentiation of short-lived monocytes into long-lived macrophages, which is essential for viral dissemination and persistence. We found that HCMV glycoproteins gB and gH directly bind and activate cellular epidermal growth factor receptor (EGFR) and integrin β1, respectively, to reshape canonical Akt signaling within monocytes. The remodeling of the Akt signaling network was due to the recruitment of nontraditional Akt activators to either the gB- or gH-generated receptor signaling complexes. Phosphoinositide 3-kinase (PI3K) comprised of the p110β catalytic subunit was recruited to the gB/EGFR complex despite p110δ being the primary PI3K isoform found within monocytes. Concomitantly, SH2 domain-containing inositol 5-phosphatase 1 (SHIP1) was recruited to the gH/integrin β1 complex, which is critical to aberrant Akt activation, as SHIP1 diverts PI3K signaling toward a noncanonical pathway. Although integrin β1 was required for SHIP1 recruitment, gB-activated EGFR mediated SHIP1 activation, underscoring the importance of the interplay between gB- and gH-mediated signaling to the unique activation of Akt during HCMV infection. Indeed, SHIP1 activation mediated the increased expression of Mcl-1 and HSP27, two Akt-dependent antiapoptotic proteins specifically upregulated during HCMV infection but not during growth factor treatment. Overall, our data indicate that HCMV glycoproteins gB and gH work in concert to initiate an HCMV-specific signalosome responsible for the atypical activation of Akt required for infected monocyte survival and ultimately viral persistence.IMPORTANCEHuman cytomegalovirus (HCMV) infection is endemic throughout the world regardless of socioeconomic conditions and geographic locations with a seroprevalence reaching up to 100% in some developing countries. Although asymptomatic in healthy individuals, HCMV can cause severe multiorgan disease in immunocompromised or immunonaive patients. HCMV disease is a direct consequence of monocyte-mediated systematic spread of the virus following infection. Because monocytes are short-lived cells, HCMV must subvert the natural short life-span of these blood cells by inducing a distinct activation of Akt, a serine/theonine protein kinase. In this work, we demonstrate that HCMV glycoproteins gB and gH work in tandem to reroute classical host cellular receptor signaling to aberrantly activate Akt and drive survival of infected monocytes. Deciphering how HCMV modulates the cellular pathway to induce monocyte survival is important to develop a new class of anti-HCMV drugs that could target and prevent spread of the virus by eliminating infected monocytes.