Elsevier

Medical Hypotheses

Volume 89, April 2016, Pages 16-20
Medical Hypotheses

Well begun is half done: Rubella virus perturbs autophagy signaling, thereby facilitating the construction of viral replication compartments

https://doi.org/10.1016/j.mehy.2016.01.011Get rights and content

Abstract

The rubella virus is the causative agent of postnatal German measles and the congenital rubella syndrome. The majority of the rubella virus replication complexes originate from the endomembrane system. The rubella virus perturbs the signaling pathways regulating the formation of autophagic membranes in the infected cells, including the Ras/Raf/MEK/ERK and PI3K/Akt pathways. It is widely accepted that these pathways inhibit autophagy. In contrast, the class III PI3K enzymes are essential for autophagy initiation. By manipulating the Ras/Raf/MEK/ERK, class I PI3K/Akt and class III PI3K axes of signal transduction, the rubella virus may differentially regulate the autophagic cascade, with consequent stimulation of the initiation and strong suppression of the later phases. Dysregulation of autophagy by this virus can have a significant impact on the construction of replication compartments by regulating membrane trafficking. We hypothesize that the rubella virus perturbs the autophagic process in order to prevent the degradation of the virus progeny, and to ensure its replication by hijacking omegasomes for the construction of the replication complexes. The virus is therefore able to utilize an antiviral mechanism to its own advantage. Therapeutic modalities targeting the autophagic process may help to ameliorate the serious consequences of the congenital rubella syndrome.

Introduction

The rubella virus (RV), a member of the Togaviridae family, is the causative agent of postnatal German measles and the congenital rubella syndrome (CRS) [1]. The slow multiplication of the virus is related to the intracellular endomembrane system. The RV enters the host cells by endocytosis. As early endosomes mature into late endosomes, acidification triggers the fusion of the viral envelope to endosomal membrane and uncoating [1]. Following decapsidation, the establishment of RV replication complexes is initiated in the cytoplasm [2]. The replication compartments have a complex structure, the central elements of which are modified endosomes, called virus factories. The RV then triggers the formation of bends and intrusions on the endosomal membrane, leading to the formation of spherules that provide a protective environment for viral RNA replication (Fig. 1) [2]. These modified endosomes subsequently recruit small endoplasmic reticulum (ER) fragments, and mitochondria, collectively termed replication complexes (Fig. 1) [2].

Although the structure of the RV replication complexes has already been fully clarified, the biogenesis of these organelle compartments remains unclear. Strikingly, the majority of the RV replication complexes originate from the endomembrane system [2]. Several steps of the RV replication cycle are closely associated with membrane-bound organelles, and this virus therefore has the possibility to alter the structure and function of the intracellular membranes in either a direct or an indirect manner. During its multiplication, the RV inhibits autophagy, triggers apoptosis, and causes a slowdown in cell cycle progression [3], [4]. Among the RV-mediated cellular effects, the dysregulation of autophagy may have the most significant impact on the construction of replication compartments via the regulation of membrane trafficking.

Autophagy is an evolutionarily conserved, cell-autonomous catabolic and defence mechanism, through which eukaryotic cells are able to recycle the long-lived cytosolic components and to degrade intracellular pathogens [5], [6]. The autophagic capture and delivery of microorganisms to the lysosomes serves as an important cellular defence mechanism, xenophagy [7]. Autophagy-inducing signals are mainly sensed and coordinated by the mammalian target of rapamycin complex 1 (mTORC1) [5]. mTORC1 inactivation leads to activation of the core autophagy machinery, the most important morphological characteristic of which is the formation of double membrane-vesicles, autophagosomes (Fig. 2) [5]. The development of the autophagosomes starts at the ER in the form of small membrane protrusions, omegasomes [8]. Following the induction of autophagy, inhibition of the mTOR leads to activation of the ULK kinase complex (UKC) at the ER membrane. The UKC then recruits the class III phosphatidylinositol 3-kinase (PI3K) complex, promoting formation of the omegasome from which the isolation membrane appears to be generated [5], [8]. The isolation membrane provides a platform for two ubiquitin-like conjugation systems involved in the elongation step of the autophagic process. The first leads to the formation of a supramolecular complex composed of Atg5/Atg12/Atg16L, while the second generates microtubule-associated protein 1 light chain 3-I (LC3-I). The Atg5/Atg12/Atg16L complex elicits the covalent conjugation of phosphatidylethanolamine to LC3-I, giving rise to the formation of LC3-II. LC3-II translocates to the isolation membrane, and facilitates its elongation. The cargo designated for degradation (e.g. a virus particle) is bound by adaptor molecules to the LC3B-II on the inner wall of the autophagosomes [5]. Autophagosomes mature into autolysosomes by sequential fusion with lysosomes in the endocytic pathway. In the developing autolysosomes, the content is degraded by hydrolases and then recycled (Fig. 2) [5]. It has been clearly demonstrated that many RNA viruses have the ability to counteract or exploit the autophagic process in order to alter the cellular physiology and metabolism for the benefit of their own replication [9].

Section snippets

Hypothesis

We hypothesize that the RV-mediated perturbation of autophagy may facilitate the construction of viral replication compartments.

Evaluation of the hypothesis

In order to determine whether perturbed autophagy contributes to the biogenesis of RV replication complexes, it is essential to demonstrate that modulation of the class III PI3K activity affects the formation of omegasomes in RV-infected cells.

To verify that class III PI3K is activated by RV infection, we plan to infect SIRC corneal cells with the To336 strain of RV at a multiplicity of infection of 5. The expression level of class III PI3K will be determined by Western blot analysis. The

Consequences of the hypothesis and discussion

The establishment of viral factories that originate from membranous intracellular organelles is essential for the multiplication of RNA viruses that have dsRNA replicative intermediates in their life cycle [13]. Many of these viruses have been shown to activate the class I PI3K/Akt signaling pathway, and to manipulate the autophagic process for their own benefit [14], [15]. These cellular effects of RNA viruses offer versatile support for viral multiplication by providing a protective

Conflict of interest statement

The authors do not have any financial or personal conflict of interest to declare.

Acknowledgements

This work was supported by the Hungarian National Development Agency (TÁMOP-4.2.2/B-10/1-2010-0012 and TÁMOP4.2.2.A-11/1/KONV-2012-0035 programs).

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