Convergent evolution in the mechanisms of ACBD3 recruitment to picornavirus replication sites

Abstract

Enteroviruses, members of the family of picornaviruses, are the most common viral infectious agents in humans causing a broad spectrum of diseases ranging from mild respiratory illnesses to life-threatening infections. To efficiently replicate within the host cell, enteroviruses hijack several host factors, such as ACBD3. ACBD3 facilitates replication of various enterovirus species, however, structural determinants of ACBD3 recruitment to the viral replication sites are poorly understood. Here, we present a structural characterization of the interaction between ACBD3 and the non-structural 3A proteins of four representative enteroviruses (poliovirus, enterovirus A71, enterovirus D68, and rhinovirus B14). In addition, we describe the details of the 3A-3A interaction causing the assembly of the ACBD3-3A heterotetramers and the interaction between the ACBD3-3A complex and the lipid bilayer. Using structure-guided identification of the point mutations disrupting these interactions, we demonstrate their roles in the intracellular localization of these proteins, recruitment of downstream effectors of ACBD3, and facilitation of enterovirus replication. These structures uncovered a striking convergence in the mechanisms of how enteroviruses and kobuviruses, members of a distinct group of picornaviruses that also rely on ACBD3, recruit ACBD3 and its downstream effectors to the sites of viral replication.

Enterovirus Replication Organelles and Inhibitors of Their Formation

“…The Q domain of ACBD3 binds to the N-terminus of PI4KB to mediate the direct, high-affinity interface between ACBD3 and PI4KB. 3A-ACBD3-PI4KB complex facilitates enterovirus replication ( Horova et al, 2019 ; Smola et al, 2020 ). However, PI4KB and ACBD3 recruitment by CVB3 and HRV 3A likely independent of GBF1/Arf1 and ACBD3 ( Dorobantu et al, 2014 , 2015 ).…”

Emerging Role for Acyl-CoA Binding Domain Containing 3 at Membrane Contact Sites During Viral Infection

“…The crystal structure of the complex of the ACBD3 GOLD domain and EV-D68 3A indicated that the GOLD-3A interaction was mediated through multiple hydrophobic interactions and hydrogen bonds (Horova et al, 2019). The alpha helices P19-V29 in 3A (α1 3A ) and Q32-K41 in 3A (α2 3A ) interacted with a shallow cavity of the GOLD domain formed by antiparallel beta strands of ACBD3.…”

“…The alpha helices P19-V29 in 3A (α1 3A ) and Q32-K41 in 3A (α2 3A ) interacted with a shallow cavity of the GOLD domain formed by antiparallel beta strands of ACBD3. The beta strand V53-I58 in 3A (β2 3A ) associated with the strand V402-P408 in ACBD3, while the beta strand I44-I46 in 3A (β1 3A ) interacted with the strand K518-R528 in ACBD3 (Horova et al, 2019). Because no direct interaction between PI4KB and the enterovirus 3A proteins has been identified, the ACBD3-PI4KB interaction stimulated by 3A and the subsequent enhancement of the membrane-targeting of PI4KB in infected cells depend on the ACBD3-3A association.…”

A Crucial Role of ACBD3 Required for Coxsackievirus Infection in Animal Model Developed by AAV-Mediated CRISPR Genome Editing Technique

“…ACBD3-knockout cells were resistant to CVB3 and blocked viral replication altogether [ 20 ]. There have been many other reports investigating the role of ACBD3 in in vitro cell culture models and structural analyses [ 21 , 22 , 23 , 24 , 25 , 26 ]. However, it has not been tested whether ACBD3 is required in the animal model of CVB3 infection.…”