The association of viral proteins with host cell dynein components during virus infection

Abstract

After fusion with the cellular plasma membrane or endosomal membranes, viral particles are generally too large to diffuse freely within the crowded cytoplasm environment. Thus, they will never reach the cell nucleus or the perinuclear areas where replication or reverse transcription usually takes place. It has been proposed that many unrelated viruses are transported along microtubules in a retrograde manner using the cellular dynein machinery or, at least, some dynein components. A putative employment of the dynein motor in a dynein-mediated transport has been suggested from experiments in which viral capsid proteins were used as bait in yeast two-hybrid screens using libraries composed of cellular proteins and dynein-associated chains were retrieved as virus-interacting proteins. In most cases DYNLL1, DYNLT1 or DYNLRB1 were identified as the dynein chains that interact with viral proteins. The importance of these dynein-virus interactions has been supported, in principle, by the observation that in some cases the dynein-interacting motifs of viral proteins altered by site-directed mutagenesis result in non-infective virions. Furthermore, overexpression of p50 dynamitin, which blocks the dynein-dynactin interaction, or incubation of infected cells with peptides that compete with viral polypeptides for dynein binding have been shown to alter the viral retrograde transport. Still, it remains to be proved that dynein light chains can bind simultaneously to incoming virions and to the dynein motor for retrograde transport to take place. In this review, we will analyse the association of viral proteins with dynein polypeptides and its implications for viral infection.

Figure 1

General architecture of the cytoplasmic dynein motor complex. The positions of DYNLL (dynein light chain LC8, green), DYNLT (dynein light chain Tctex, yellow), DYNLRB (dynein light chain roadblock, dark blue), DYNC1I (dynein intermediate chain, violet; the carboxy‐terminal WD40 repeat (β‐propeller) is depicted as a heptagon), DYNC1L (dynein light intermediate chain, light blue) and DYNC1H (dynein heavy chain, red) are shown. The crystallographic structures of the DYNLT1 homodimer (yellow) and DYNLL1 homodimer (green) binding to adjacent sequences from the dynein intermediate chain (violet) are shown at the bottom (PDB accession number http://www.rcsb.org/pdb/search/structidSearch.do?structureId=3FM7). In addition, the crystallographic structure of the DYNLRB homodimer (PDB accession number http://www.rcsb.org/pdb/search/structidSearch.do?structureId=3L9K) depicted in blue is shown on top. Note that the crystal structure of the motor domain of the dynein heavy chain has also been recently reported [119].

Figure 2

Viral retrograde transport model. Both the entry of the viral particle through the endosome pathway (A, C) and the direct fusion of the viral envelope to the plasma membrane (B) lead to the retrograde transport along microtubules using the cytoplasmic the dynein motor. Viral capsid proteins might associate to dynein directly (A) or a cellular receptor might bind simultaneously to a viral protein and the dynein motor (C). After reaching the MTOC at the microtubular minus end viruses are uncoated and directed to the sites of replication, production and assembly of the new viral proteins (D) such as the nucleus or the viral factories. The newly assembled particles might become transported to the cell periphery by the anterograde transport machinery.

Figure 3

(A) Model for the interaction of a generic viral capsid with cytoplasmic, non‐microtubule‐associated DYNLL. It is then conceivable that the DYNLL homodimer might bind simultaneously to two viral polypeptides when part of the viral capsid (a) or when soluble after viral disassembly (b). This is in agreement with the modeled solution structure of the complex of DYNLL1 with p54 of ASFV [26]. (B) Three hypotheses for the association of viral proteins to the dynein molecular motor. One viral polypeptide displaces a dynein intermediate chain from one binding side of the DYNLL homodimer (a). Two DYNLL homodimers associate to one dynein intermediate chain and to one viral polypeptide simultaneously (b). Binding of the viral polypeptides displaces the dynein intermediate chains from the DYNLL binding grooves but DYNLL remains part of the dynein motor through the binding to the dynein heavy chain (red) (c).