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首页> 外文期刊>Cellular Signalling >TMC8 (EVER2) attenuates intracellular signaling by Zn~(2+) and Ca~(2+) and suppresses activation of Cl~- currents
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TMC8 (EVER2) attenuates intracellular signaling by Zn~(2+) and Ca~(2+) and suppresses activation of Cl~- currents

机译：TMC8（EVER2）减弱Zn〜（2+）和Ca〜（2+）的细胞内信号传导并抑制Cl〜-电流的激活

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摘要

Eight paralogue members form the family of transmembrane channel-like (TMC) proteins that share considerable sequence homology to anoctamin 1 (Ano1, TMEM16A). Ano1 is a Ca~(2+) activated Cl~- channel that is related to head and neck cancer, often caused by human papilloma virus (HPV) infection. Mutations in TMC 6 and 8 (EVER1, EVER2) cause epidermodysplasia verruciformis. This rare skin disease is characterized by abnormal susceptibility to HPV infection and cancer.We found that in contrast to Ano1 the common paralogues TMC4-TMC8 did not produce Ca~(2+) activated Cl~- currents when expressed in HEK293 cells. On the contrary, TMC8 was found to be localized in the endoplasmic reticulum (ER), where it inhibited receptormediated Ca~(2+) release, activation of Ano1 and volume regulated LRRC8-related Cl~- currents. Zn~(2+) is co-released from the ER together with Ca~(2+) and thereby further augments Ca~(2+) store release. Because TMC8 is required to lower cytosolic Zn~(2+) concentrations by the Zn~(2+) transporter ZnT-1, we hypothesize that HPV infections and cancer caused by mutations in TMC8 are related to upregulated Zn~(2+)/Ca~(2+) signaling and activation of Ano1.
机译：八个旁系成员形成跨膜通道样（TMC）蛋白质家族，它们与八环素1（Ano1，TMEM16A）具有相当的序列同源性。 Ano1是由Ca〜（2+）激活的Cl〜-通道，与头颈癌有关，通常由人乳头瘤病毒（HPV）感染引起。 TMC 6和8（EVER1，EVER2）中的突变会导致疣状表皮增生。这种罕见的皮肤疾病的特征是对HPV感染和癌症的易感性异常。我们发现，与Ano1相比，普通旁系动物TMC4-TMC8在HEK293细胞中表达时不会产生Ca〜（2+）激活的Cl〜-电流。相反，发现TMC8位于内质网（ER）中，在那里它抑制受体介导的Ca〜（2+）释放，Ano1的激活和与体积有关的LRRC8相关Cl〜-电流。 Zn〜（2+）与Ca〜（2+）一起从ER中共同释放，从而进一步增加Ca〜（2+）的存储释放。由于需要Zn〜（2+）转运蛋白ZnT-1降低TMC8降低胞质中的Zn〜（2+）浓度，因此我们假设由TMC8突变引起的HPV感染和癌症与Zn〜（2 +）/ Ca〜（2+）信号传导和Ano1的激活。

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