Autophagy hijacked through viroporin-activated calcium/calmodulin-dependent kinase kinase-β signaling is required for rotavirus replication

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):E3405-13. doi: 10.1073/pnas.1216539109. Epub 2012 Nov 26.


Autophagy is a cellular degradation process involving an intracellular membrane trafficking pathway that recycles cellular components or eliminates intracellular microbes in lysosomes. Many pathogens subvert autophagy to enhance their replication, but the mechanisms these pathogens use to initiate the autophagy process have not been elucidated. This study identifies rotavirus as a pathogen that encodes a viroporin, nonstructural protein 4, which releases endoplasmic reticulum calcium into the cytoplasm, thereby activating a calcium/calmodulin-dependent kinase kinase-β and 5' adenosine monophosphate-activated protein kinase-dependent signaling pathway to initiate autophagy. Rotavirus hijacks this membrane trafficking pathway to transport viral proteins from the endoplasmic reticulum to sites of viral replication to produce infectious virus. This process requires PI3K activity and autophagy-initiation proteins Atg3 and Atg5, and it is abrogated by chelating cytoplasmic calcium or inhibiting calcium/calmodulin-dependent kinase kinase-β. Although the early stages of autophagy are initiated, rotavirus infection also blocks autophagy maturation. These studies identify a unique mechanism of virus-mediated, calcium-activated signaling that initiates autophagy and hijacks this membrane trafficking pathway to transport viral proteins to sites of viral assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / physiology*
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Calcium Signaling
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / physiology*
  • Cell Line
  • Cells, Cultured
  • Enzyme Activation
  • Glycoproteins / physiology
  • Macaca mulatta
  • Mice
  • Mice, Knockout
  • Microtubule-Associated Proteins / deficiency
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / physiology
  • Protein Transport
  • Rotavirus / pathogenicity
  • Rotavirus / physiology*
  • Signal Transduction
  • Toxins, Biological / physiology
  • Ubiquitin-Conjugating Enzymes / deficiency
  • Ubiquitin-Conjugating Enzymes / genetics
  • Ubiquitin-Conjugating Enzymes / physiology
  • Unfolded Protein Response
  • Viral Nonstructural Proteins / physiology
  • Virus Assembly / physiology
  • Virus Replication / physiology*


  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • Glycoproteins
  • Microtubule-Associated Proteins
  • NS28 protein, rotavirus
  • Toxins, Biological
  • Viral Nonstructural Proteins
  • Ubiquitin-Conjugating Enzymes
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Atg3 protein, mouse