Abstract

Influenza A virus (IAV) enters host cells by endocytosis followed by acid-activated penetration from late endosomes (LEs). Using siRNA silencing, we found that histone deacetylase 8 (HDAC8), a cytoplasmic enzyme, efficiently promoted productive entry of IAV into tissue culture cells, whereas HDAC1 suppressed it. HDAC8 enhanced endocytosis, acidification, and penetration of the incoming virus. In contrast, HDAC1 inhibited acidification and penetration. The effects were connected with dramatic alterations in the organization of the microtubule system, and, as a consequence, a change in the behavior of LEs and lysosomes (LYs). Depletion of HDAC8 caused loss of centrosome-associated microtubules and loss of directed centripetal movement of LEs, dispersing LE/LYs to the cell periphery. For HDAC1, the picture was the opposite. To explain these changes, centrosome cohesion emerged as the critical factor. Depletion of HDAC8 caused centrosome splitting, which could also be induced by depleting a centriole-linker protein, rootletin. In both cases, IAV infection was inhibited. HDAC1 depletion reduced the splitting of centrosomes, and enhanced infection. The longer the distance between centrosomes, the lower the level of infection. HDAC8 depletion was also found to inhibit infection of Uukuniemi virus (a bunyavirus) suggesting common requirements among late penetrating enveloped viruses. The results established class I HDACs as powerful regulators of microtubule organization, centrosome function, endosome maturation, and infection by IAV and other late penetrating viruses.

Highlights

  • To enter their host cells, the majority of animal viruses take advantage of the cell’s endocytic machinery

  • While analyzing the role of cell factors in influenza A virus entry into host cells, we observed that depletion of members of the class I histone deacetylases (HDACs) family dramatically affected the efficiency of infection

  • Depletion of HDACs 8 and 3 decreased, and depletion of HDAC1 elevated the efficiency of entry

Read more

Summary

Introduction

To enter their host cells, the majority of animal viruses take advantage of the cell’s endocytic machinery. Since endocytosis and endosome maturation are complex and tightly regulated activities, successful entry and infection relies on numerous cellular factors and processes. This is clearly illustrated by recent high-throughput siRNA screens that have identified hundreds of host cell genes required for infection by different viruses [1,2]. Infection begins by virus binding to sialic acid residues on cell surface glycoproteins and lipids followed by internalization either via clathrin-mediated endocytosis or a clathrin-independent, macropinocytosis-like uptake process [4,5,6,7]. Penetration of the genome into the cytosol is mediated by the hemagglutinin (HA) glycoprotein, an acid-activated membrane fusion factor [8]. The matrix protein (M1) dissociates, and the viral ribonucleoproteins (vRNPs) are imported via nuclear pore complexes into the nucleus where replication and transcription take place [11,12]

Methods
Results
Discussion
Conclusion
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call