Human Parainfluenza Virus Type 2 V Protein Modulates Iron Homeostasis
Human Parainfluenza Virus Type 2 V Protein Modulates Iron Homeostasis
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DOI：
10.1128/jvi.01861-20
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发表时间：
2021-01
影响因子：
5.4
通讯作者：
K. Ohta;N. Saka;M. Nishio
中科院分区：
文献类型：
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作者：
K. Ohta;N. Saka;M. Nishio
hPIV-2 V蛋白干扰FTH 1和NCOA 4之间的相互作用，并抑制NCOA 4介导的铁蛋白降解，从而抑制铁释放到细胞质中。这种铁稳态调节允许感染细胞避免凋亡性细胞死亡，从而导致hPIV-2的有效生长。摘要细胞内铁浓度是细胞生存力的关键。已知它会影响几种病毒的生长，但其分子机制尚不清楚。我们发现铁螯合剂抑制人副流感病毒2型（hPIV-2）的生长。此外，感染hPIV-2改变铁蛋白定位从颗粒均匀分布在细胞质内的铁刺激的细胞。hPIV-2的V蛋白与铁蛋白重链1（FTH 1）（一种铁蛋白亚基）相互作用。它还与核受体辅激活因子4（NCOA 4）结合，NCOA 4介导铁蛋白的自噬降解，即所谓的铁蛋白吞噬。因此，V蛋白干扰FTH 1和NCOA 4之间的相互作用。hPIV-2生长在FTH 1敲减细胞系中受到抑制，其中显示出严重的hPIV-2诱导的细胞凋亡。相比之下，NCOA 4敲低导致促进hPIV-2生长和有限的凋亡。我们的数据共同表明，hPIV-2 V蛋白抑制FTH 1-NCOA 4相互作用和随后的铁蛋白吞噬。这种铁稳态调节允许感染细胞避免凋亡性细胞死亡，从而导致hPIV-2的有效生长。重要性hPIV-2 V蛋白干扰FTH 1和NCOA 4之间的相互作用，并抑制NCOA 4介导的铁蛋白降解，从而抑制铁释放到细胞质中。这种铁稳态调节允许感染细胞避免凋亡性细胞死亡，从而导致hPIV-2的有效生长。
hPIV-2 V protein interferes with interaction between FTH1 and NCOA4 and inhibits NCOA4-mediated ferritin degradation, leading to the inhibition of iron release to the cytoplasm. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2. ABSTRACT Intracellular iron concentration is tightly controlled for cell viability. It is known to affect the growth of several viruses, but the molecular mechanisms are not well understood. We found that iron chelators inhibit growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, infection with hPIV-2 alters ferritin localization from granules to a homogenous distribution within cytoplasm of iron-stimulated cells. The V protein of hPIV-2 interacts with ferritin heavy chain 1 (FTH1), a ferritin subunit. It also binds to nuclear receptor coactivator 4 (NCOA4), which mediates autophagic degradation of ferritin, so-called ferritinophagy. V protein consequently interferes with interaction between FTH1 and NCOA4. hPIV-2 growth is inhibited in FTH1 knockdown cell line where severe hPIV-2-induced apoptosis is shown. In contrast, NCOA4 knockdown results in the promotion of hPIV-2 growth and limited apoptosis. Our data collectively suggest that hPIV-2 V protein inhibits FTH1-NCOA4 interaction and subsequent ferritinophagy. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2. IMPORTANCE hPIV-2 V protein interferes with interaction between FTH1 and NCOA4 and inhibits NCOA4-mediated ferritin degradation, leading to the inhibition of iron release to the cytoplasm. This iron homeostasis modulation allows infected cells to avoid apoptotic cell death, resulting in effective growth of hPIV-2.