Co-option of Membrane Wounding Enables Virus Penetration into Cells

• Published in: Cell host & microbe 2015-07, Vol.18 (1), p.75-85
• Main Authors: Luisoni, Stefania, Suomalainen, Maarit, Boucke, Karin, Tanner, Lukas B., Wenk, Markus R., Guan, Xue Li, Grzybek, Michał, Coskun, Ünal, Greber, Urs F.
• Format: Article
• Language: English
• Subjects: Adenoviridae - enzymology; Adenoviridae - physiology; Biotransformation; Capsid Proteins - metabolism; Cell Membrane - metabolism; Cell Membrane - physiology; Ceramides - metabolism; Endocytosis; Exocytosis; HeLa Cells; Host-Pathogen Interactions; Humans; Lysosomes - metabolism; Sphingomyelin Phosphodiesterase - metabolism; Sphingomyelins - metabolism; Virus Internalization
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2015.06.006

During cell entry, non-enveloped viruses undergo partial uncoating to expose membrane lytic proteins for gaining access to the cytoplasm. We report that adenovirus uses membrane piercing to induce and hijack cellular wound removal processes that facilitate further membrane disruption and infection. Incoming adenovirus stimulates calcium influx and lysosomal exocytosis, a membrane repair mechanism resulting in release of acid sphingomyelinase (ASMase) and degradation of sphingomyelin to ceramide lipids in the plasma membrane. Lysosomal exocytosis is triggered by small plasma membrane lesions induced by the viral membrane lytic protein-VI, which is exposed upon mechanical cues from virus receptors, followed by virus endocytosis into leaky endosomes. Chemical inhibition or RNA interference of ASMase slows virus endocytosis, inhibits virus escape to the cytosol, and reduces infection. Ceramide enhances binding of protein-VI to lipid membranes and protein-VI-induced membrane rupture. Thus, adenovirus uses a positive feedback loop between virus uncoating and lipid signaling for efficient membrane penetration. [Display omitted] •Membrane lytic adenovirus protein-VI is exposed on incoming virus at the plasma membrane•VI triggers calcium ion influx through small membrane pores and lysosomal exocytosis•Lysosomal acid sphingomyelinase boosts ceramide lipid levels and virus endocytosis•Ceramide lipids favor membrane binding of VI and virus rupture of endosomes Non-enveloped viruses expose membrane lytic proteins to gain access to the cytoplasm. Luisoni et al. present evidence that small pores induced by the adenovirus membrane lytic protein-VI trigger calcium-mediated lysosomal exocytosis repair pathways and lipid signaling that facilitate virus entry and infection.