Download Double-membrane vesicles: All autophagosomes?

Double-membrane vesicles: All
autophagosomes?
Fulvio Reggiori,
Department of Cell Biology, University Medical
Centre Utrecht, Utrecht, The Netherlands
Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses that
infect the mammalian respiratory and gastrointestinal tracts with
mechanisms that are poorly characterized. The relevance of this family of
viruses has considerably increased due to their recent emerging as the
cause of the severe acute respiratory syndrome (SARS). In 2003, an
epidemic outbreak of the SARS CoVs (SARS-CoV) in South East Asia
and Canada sickened more than 8,000 people and killed nearly 800 of
them. Two additional new human CoVs, HCoV-NL63 and HCoV-HKU1, have recently been discovered and because this family of viruses is characterized by
frequent host-shifting events including zoonosis (animal-to-human), CoVs are a threat for the
human health. Unfortunately, an effective therapy against these pathogens, which also causes
considerable losses in the livestock industry, does not exist.
Upon entering the host cells, CoVs induce the formation of double-membrane vesicles
(DMVs). These structures are vital for the virus because harboring the viral replication and
transcription complexes. While it has been proposed that these DMVs are autophagosomes,
the hallmark of autophagy, their subcellular origin remains unknown but a recent study has
indicated that they could be derived from the endoplasmic reticulum (ER). The ER is the
organelle where proteins are translated and folded before being sent to the extracellular space,
plasma membrane and other subcellular organelles. When proteins fail to acquire their final
correct conformation, they are rapidly removed from the ER by a system known as the ERassociated degradation (ERAD). Under normal growing conditions, the activity of this
degradative pathway is maintained at minimal levels to avoid the disposal of correctly folded
proteins. It has been shown that this is achieved by eliminating two positive ERAD regulators
from the ER lumen through a transport route has been named the ERAD tuning and involve
vesicle called EDEMosomes. The mechanism underlying this pathway has still to be
characterized but we have recently demonstrated that the mouse hepatitis virus (MHV), the
CoVs that we use as a model, hijacks the EDEMosomes to generate its replicative DMVs
rather than autophagosomes. The molecular principles of this hijacking, however, remain
completely unknown. The elucidation of these principles has become of primary interest
because we have shown that inhibition of the ERAD tuning completely blocks MHV
infection. This discovery has thus unveiled a possible way of therapeutically fight CoVs
infections. Importantly, initial observations indicate that SARS-CoV is probably using the
same expedient to invade host cells.