Recycling Endosomes and Viral Infection

Abstract

Many viruses exploit specific arms of the endomembrane system. The unique composition of each arm prompts the development of remarkably specific interactions between viruses and sub-organelles. This review focuses on the viral-host interactions occurring on the endocytic recycling compartment (ERC), and mediated by its regulatory Ras-related in brain (Rab) GTPase Rab11. This protein regulates trafficking from the ERC and the trans-Golgi network to the plasma membrane. Such transport comprises intricate networks of proteins/lipids operating sequentially from the membrane of origin up to the cell surface. Rab11 is also emerging as a critical factor in an increasing number of infections by major animal viruses, including pathogens that provoke human disease. Understanding the interplay between the ERC and viruses is a milestone in human health. Rab11 has been associated with several steps of the viral lifecycles by unclear processes that use sophisticated diversified host machinery. For this reason, we first explore the state-of-the-art on processes regulating membrane composition and trafficking. Subsequently, this review outlines viral interactions with the ERC, highlighting current knowledge on viral-host binding partners. Finally, using examples from the few mechanistic studies available we emphasize how ERC functions are adjusted during infection to remodel cytoskeleton dynamics, innate immunity and membrane composition.

Keywords: Rab GTPases; Rab11; animal viruses; intracellular membranes; phosphoinositides; recycling endosome.

Figure 1

The endomembrane system of the eukaryotic cell and major Ras-related in brain (Rab) GTPases and phosphoinositides occupying its subdomains. (A) The eukaryotic cell is composed of several compartments. Trajectory of endocytosed material is depicted in blue arrows. Upon internalization, cargo is transported to the early endosome (EE), and either degraded upon passage through late endosomes (LE), endolysosomes (EL) and lysosomes (L), or recycled via a fast or a slow pathway that requires transfer from EE to endocytic recycling compartment (ERC). Secretory pathways from the trans-Golgi network (TGN) to the plasma membrane are highlighted in red. Note that at some points, exocytic and endocytic pathways intertwine. Rab GTPases and phosphoinositides occupy specific subcellular locations and are marked adjacent to corresponding compartments. Phosphatidylinositol-3-phosphate (PI3P) is highlighted in orange to facilitate illustration of its selective inclusion in internal luminal vesicles of LE; (B) The chemical structure of phosphatidylinositol is shown, highlighting carbon number of the sugar moiety in red. Fatty acids (R1, R2) in the glycerol moiety allow ligation to membranes. Carbon 3, 4 and 5 can be additionally phosphorylated by esterification of hydroxyl groups to originate seven isoforms, shown in the table. Isoforms found in the ERC (despite in minor amounts) are highlighted in red. Abbreviations include: PI4P: phosphatidylinositol-4-phosphate; PIP5: phosphatidylinositol-5-phosphate; PI3,5P2: phosphatidylinositol-3,5-biphosphate; PI3,4P2: phosphatidylinositol-3,4-biphosphate; PI4,5P2: phosphatidylinositol-4,5-biphosphate; PI3,4,5P3: phosphatidylinositol-3,4,5- triphosphate.

Figure 2

Rab GTPase spatial and temporal regulation. (A) Activation of Rab GTPases occurs through the exchange of GDP by GTP, a process catalyzed by guanine nucleotide exchange factors (GEFs), with a concomitant conformational change (1). Active Rabs attract multiple effectors and can be converted to the inactive state through GTP hydrolysis (2), which is accelerated by GTPase-activating proteins (GAPs). In certain circumstances, the recruitment of Rabs to membranes can bypass activation by Rab-GEFs. Activated ADP ribosylation factor (ARF) binds its cargo, and the dimer recruits the ARF GAP. The newly formed trimer has also affinity for an effector of a Rab, establishing a crosstalk between a ARF and a Rab (3). Alternatively, post-translational modifications can also regulate Rab function (4). High cholesterol content in membranes can reduce Rab extraction from membranes by inhibiting the activity of the corresponding guanine nucleotide dissociation inhibitory proteins (GDI) (5); (B) Rab GTPase conversion cascades are flexible mechanisms that allow crosstalk between Rabs. The activation (1) or inactivation (2) of a particular Rab can be made by a GEF or GAP, respectively, that was recruited by another Rab that acts upstream. The same Rab can also recruit its own GEF to maintain the activation state by positive feedback loop (1). Distinct Rabs can bind the same effector (3), a process called effector coupling.

Figure 3

Phosphoinositide cascades. The phosphoinositide-mediated recruitment of kinases (A) or phosphatases (B) to act upon other phosphoinositides can initiate the formation of protein scaffolds, which regulate downstream membrane trafficking events.

Figure 4

Rab11 cycle in vesicular transport (steps in Rab11 cycle are numbered from 1 to 6).

Figure 5

Involvement of the ERC in viral entry in the host cell. Upon entry, viruses can be trafficked from the EE to the ERC or to LE. Others can bypass EE and be directed to the ERC for viral uncoating.

Figure 6

Involvement of the ERC in viral assembly, budding and release. The ERC can be used by different viruses for transport of viral genome particles and proteins towards assembly sites. Moreover, it is also involved in the transport of entire virions to the cell surface.