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Overexpressed coiled-coil domain containing protein 8 (CCDC8) mediates newly synthesized HIV-1 Gag lysosomal degradation.
Sci Rep. 2020 Jul 10; 10(1):11416.SR

Abstract

Normally, HIV-1 enters into CD4+ cells through membrane fusion, and newly synthesized HIV-1 viral proteins assemble on the plasma membrane to form viral particles and bud out. In the previous study, we found host factor coiled-coil domain containing protein 8 (CCDC8) can strongly inhibit HIV-1 production, but the underline mechanism is not clear. Here we show that overexpression of CCDC8 reverses the normal HIV-1 production process, and causes newly assembled HIV-1 Gag particles to be endocytosed on the plasma membrane, rather than budding out. Live-cell imaging system captured the moment of CCDC8-mediated Gag internalization on the plasma membrane, and the speed of Gag turnover is up to 1.53 μm/s, much faster than Gag assembly on the plasma membrane. After Gag internalization, it accumulates in the cellular organelle-lysosome for degradation, but not proteasome, autophagosome, endoplasmic reticulum, clathrin or recycling endosome. In addition, CCDC8 is a membrane-associated protein, and N-terminal of CCDC8 is very important for membrane binding, and also important for inhibition of Gag assembly. C-terminal deletion of CCDC8 has a little effect on anti-HIV-1 effect. Moreover, CCDC8 is phosphorylated at amino acid threonine T87 and serine S261, and mono-methylated at lysine K491. Alanine mutations of T87A, S261A and K491A singly or in combination do not affect CCDC8 anti-HIV activity. In conclusion, overexpression of CCDC8 can cause newly assembled HIV-1 Gag particles on the plasma membrane to be endocytosed and degraded in lysosome.

Authors+Show Affiliations

School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China.School of Medicine, Nankai University, Tianjin, China. weimin@nankai.edu.cn. Nankai University Second People's Hospital, School of Medicine, Nankai University, Tianjin, China. weimin@nankai.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32651437

Citation

Jiang, Xiangxiang, et al. "Overexpressed Coiled-coil Domain Containing Protein 8 (CCDC8) Mediates Newly Synthesized HIV-1 Gag Lysosomal Degradation." Scientific Reports, vol. 10, no. 1, 2020, p. 11416.
Jiang X, Jia X, Sun J, et al. Overexpressed coiled-coil domain containing protein 8 (CCDC8) mediates newly synthesized HIV-1 Gag lysosomal degradation. Sci Rep. 2020;10(1):11416.
Jiang, X., Jia, X., Sun, J., Qi, C., Lu, L., Wang, Y., Zhang, L., & Wei, M. (2020). Overexpressed coiled-coil domain containing protein 8 (CCDC8) mediates newly synthesized HIV-1 Gag lysosomal degradation. Scientific Reports, 10(1), 11416. https://doi.org/10.1038/s41598-020-68341-3
Jiang X, et al. Overexpressed Coiled-coil Domain Containing Protein 8 (CCDC8) Mediates Newly Synthesized HIV-1 Gag Lysosomal Degradation. Sci Rep. 2020 Jul 10;10(1):11416. PubMed PMID: 32651437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Overexpressed coiled-coil domain containing protein 8 (CCDC8) mediates newly synthesized HIV-1 Gag lysosomal degradation. AU - Jiang,Xiangxiang, AU - Jia,Xiaopeng, AU - Sun,Jinhuan, AU - Qi,Chunxia, AU - Lu,Lingling, AU - Wang,Yanfeng, AU - Zhang,Lei, AU - Wei,Min, Y1 - 2020/07/10/ PY - 2020/01/16/received PY - 2020/06/16/accepted PY - 2020/7/12/entrez PY - 2020/7/12/pubmed PY - 2020/7/12/medline SP - 11416 EP - 11416 JF - Scientific reports JO - Sci Rep VL - 10 IS - 1 N2 - Normally, HIV-1 enters into CD4+ cells through membrane fusion, and newly synthesized HIV-1 viral proteins assemble on the plasma membrane to form viral particles and bud out. In the previous study, we found host factor coiled-coil domain containing protein 8 (CCDC8) can strongly inhibit HIV-1 production, but the underline mechanism is not clear. Here we show that overexpression of CCDC8 reverses the normal HIV-1 production process, and causes newly assembled HIV-1 Gag particles to be endocytosed on the plasma membrane, rather than budding out. Live-cell imaging system captured the moment of CCDC8-mediated Gag internalization on the plasma membrane, and the speed of Gag turnover is up to 1.53 μm/s, much faster than Gag assembly on the plasma membrane. After Gag internalization, it accumulates in the cellular organelle-lysosome for degradation, but not proteasome, autophagosome, endoplasmic reticulum, clathrin or recycling endosome. In addition, CCDC8 is a membrane-associated protein, and N-terminal of CCDC8 is very important for membrane binding, and also important for inhibition of Gag assembly. C-terminal deletion of CCDC8 has a little effect on anti-HIV-1 effect. Moreover, CCDC8 is phosphorylated at amino acid threonine T87 and serine S261, and mono-methylated at lysine K491. Alanine mutations of T87A, S261A and K491A singly or in combination do not affect CCDC8 anti-HIV activity. In conclusion, overexpression of CCDC8 can cause newly assembled HIV-1 Gag particles on the plasma membrane to be endocytosed and degraded in lysosome. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/32651437/Overexpressed_coiled-coil_domain_containing_protein_8_(CCDC8)_mediates_newly_synthesized_HIV-1_Gag_lysosomal_degradation L2 - http://dx.doi.org/10.1038/s41598-020-68341-3 DB - PRIME DP - Unbound Medicine ER -
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