The invasion of tobacco mosaic virus RNA induces endoplasmic reticulum stress-related autophagy in HeLa cells

Li, Li; Wang, Li; Xiao, Ruijing; Zhu, Guoguo; Li, Yan; Liu, Changxuan; Yang, Ru; Tang, Zhiqing; Li, Jie; Huang, Wei; Chen, Lang; Zheng, Xiaoling; He, Yuling; Tan, Jinquan

experience ERS and activate ER chaperones (such as GRP78 in the ER lumen) to increase protein folding capacity. If enough TMV proteins are produced so that the capacity of GRP78 is exceeded, ERS stimulates the ends of ER membranes to expand to maximize sequestration into vacuoles in which TMV proteins (such as CP) might be produced. These new vacuoles are wrapped rapidly by phagophores (which also likely originate from the ER and look like the forks in our electron micrographs) that further form autophagosomes. Finally, with the fusion of autophagosomes and lysosomes, autolysosomes form to digest the vacuolar contents; we suggest that these vacuolar contents might not be digested, but instead, immune escape occurs through some unknown molecular mechanism. The latter assertion is supported by our evidence of the accumulation of TMV proteins on and around autophagosomal membranes, by the increased CP in the ER and by the enrichment of TMV-positive RNA in the nucleolus. In conclusion, TMV-RNA induces ERS-related autophagy in HeLa cells, and a potential defence mechanism involving ERS and ERS-related autophagy utilized by HeLa cells against TMV-RNA is modelled in Figure 7 . Figure 7 Schematic diagram of the potential ERS-related autophagic defence mechanism utilized by HeLa cells against TMV-RNA After TMV-RNA enters HeLa cells, it is translated into protein by ribosomes located on the ER membrane. TMV proteins, such as CP , will likely be recognized as foreign or unfolded proteins in the ER lumen and trigger ERS. GRP78 is a marker of ERS, is highly expressed and acts as a chaperone to assist in the folding of CP . If the quantity of CP is too great, GRP78 might leave CP and stimulate the distal end of ER membranes to expand and swell to sequester CP into vacuoles. These new vacuoles would be enwrapped rapidly by phagophores, which likely originate from the ER. These new phagophores resemble forks extending towards the vacuole, and they engulf it to promote maturation into double-membrane autophagosomes. Finally, by fusion with a lysosome, autophagosomes become mono-membrane-structured autolysosomes.