Emerging roles for ubiquitin in adenovirus cell entry

Abstract

Adenovirus relies on numerous interactions between viral and host cell proteins to efficiently enter cells. Undoubtedly, post-translational modifications of host and cellular proteins can impact the efficiency of this cell entry process. Ubiquitylation, once simply thought of as a modification targeting proteins for proteasomal degradation, is now known to regulate protein trafficking within cells, protein-protein interactions and cell signalling pathways. Accumulating evidence suggests that protein ubiquitylation can influence all stages of the life cycle of other viruses such as cell entry, replication and egress. Until recently, the influence of ubiquitylation has only been documented during adenovirus replication. This review highlights the most recent evidence demonstrating direct engagement of host ubiquitylation and SUMOylation machinery by adenovirus during cell entry. Additionally, potential roles for host protein ubiquitylation and the potential for adenovirus regulation of host ubiquitylation machinery during cell entry are discussed.

Figure 1. Adenovirus capsid structure

Diagram showing the 7 capsid proteins plus the L3-23K protease. Protein IIIa, protein VI and protein VIII are located in the interior of the capsid. Also contained in the capsid is the L3-23K protease/AVP. Not shown are the Terminal protein, Protein Mu, Protein VII, and Protein V, where are all associated with the viral DNA (also not shown). Adapted from (Nemerow et al., 2009)

Figure 2. Potential roles for ubiquitlyation during adenovirus cell entry

A) Protein VI contains a conserved PPxY motif, responsible for colocalization with Nedd4 family members of E3-ubiquitin ligases and in vitro pVI ubiquitylation. Mutation of the PPxY motif decreases specific infectivity at an entry step post endosomal escape. B) The penton base contains 2 conserved PPxY motifs, and Nedd4 E3-ubiquitin ligase family members bind penton base via the PPxY motifs. Additionally, penton base binds BAG3 in a PPxY-dependent manner. BAG3 knockdown decreases adenovirus specific infectivity. C) L3-23K protease/Avp activity is required during adenovirus cell entry. Avp possesses deubiquitylating activity, but it has not been determined if the deubiquitylating activity is required for adenovirus specific infectivity. D) CAR associates with the E3-ubiquitin ligase LNX. Not shown-MG132 treatment increases CAR surface expression and increases adenovirus infectivity. E) Treatment with MG132 decreases adenovirus infectivity for viruses that utilize the CD46 receptor. F) Upon adenovirus binding to α_vβ₃ integrins, integrin ubiquitlyation and trafficking to lysosomes (LAMP1) may occur.