ALV-J inhibits autophagy through the GADD45ß/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy

Authors: LIAO, ZHIHONG - South China Agricultural Univerisity; ZHANG, XINHENG - South China Agricultural Univerisity; SONG, CAILIANG - South China Agricultural Univerisity; LIN, WENCHENG - South China Agricultural Univerisity; CHEN, YUZHEN - Jinan University; XIE, ZI - South China Agricultural Univerisity; CHEN, SHENG - South China Agricultural Univerisity; NIE, YU - South China Agricultural Univerisity; LI, ALJUN - Jinan University; Zhang, Huanmin; LI, HONGXIN - South China Agricultural Univerisity; LI, HAIYUN - South China Agricultural Univerisity; XIE, QINGMEI - South China Agricultural Univerisity

Submitted to: Cell Death & Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/29/2020
Publication Date: 8/12/2020
Citation: Liao, Z., Zhang, X., Song, C., Lin, W., Chen, Y., Xie, Z., Chen, S., Nie, Y., Li, A., Zhang, H., Li, H., Li, H., Xie, Q. 2020. ALV-J inhibits autophagy through the GADD45ß/MEKK4/P38MAPK signaling pathway and mediates apoptosis following autophagy. Cell Death & Disease. 11:684. https://doi.org/10.1038/s41419-020-02841-y.
DOI: https://doi.org/10.1038/s41419-020-02841-y

Interpretive Summary: Autophagy is a natural and regulated process of cell, which removes unnecessary or dysfunctional components from body. This process also enables abnormal consumption of the body’s own tissue through metabolic processes under starvation or disease conditions. Subgroup J avian leukosis virus (ALV-J) is an oncogenic avian retrovirus, which causes tumor formation in susceptible chickens and is reportedly involved in autophagy. In this study, through comprehensive laboratory tests and examinations, we found a piece of new evidence that ALV-J through a series of actions among molecules in a cell to regulate the autophagy processes, which is scientifically known as the GADD45ß/MEKK4/p38MAPK signaling pathway. This finding is of importance since it advances the scientific understanding on the underline mechanism associated with ALV-infection and autophagy processes.

Technical Abstract: Autophagy and apoptosis, which are important processes for host immunity, are commonly exploited by viruses to facilitate their survival. However, to the best of our knowledge, very few studies have researched on the mechanisms of action of the autophagic and apoptotic signaling pathways following viral infection. This study was aimed to investigate the mechanisms of action of growth arrest and DNA-damage-inducible ß (GADD45ß), an important resistance gene involved in the host resistance to ALV-J. Both ALV-J infection and the overexpression of GADD45ß inhibited autophagy during the early stages, which prevented the autophagosomes from binding to the lysosomes and resulted in an incomplete autophagic flux. Notably, GADD45ß was discovered to interact with MEKK4 in DF-1 cells. The genetic knockdown of GADD45ß and MEKK4 using small interfering RNA affected ALV-J infection, which suggested that ALV-J may promote the binding of GADD45ß to MEKK4 to activate the p38MAPK signaling pathway that subsequently inhibits autophagy. Furthermore, ALV-J was revealed to affect the autophagic pathway prior to affecting the apoptotic pathway. In conclusion, to the best of our knowledge, the present study is the first to investigate the combined effects of ALV-J infection on autophagy and apoptosis, and to suggest that ALV-J inhibits autophagy via the GADD45ß/MEKK4/p38MAPK signaling pathway.