E1 empty set E4 protein of human papillomavirus type 16 associates with mitochondria
Related Experiment Video
Updated: Aug 23, 2026
In situ Subcellular Fractionation of Adherent and Non-adherent Mammalian Cells
Published on: July 23, 2010
Kenneth Raj1, Samuel Berguerand, Shirley Southern
1Swiss Institute for Experimental Cancer Research and NCRR Molecular Oncology, 1066 Epalinges, Switzerland.
Abstract:
The human papillomavirus (HPV) E1 empty set E4 protein is the most abundantly expressed viral protein in HPV-infected epithelia. It possesses diverse activities, including the ability to bind to the cytokeratin network and to DEAD-box proteins, and in some cases induces the collapse of the former. E1 empty set E4 is also able to prevent the progression of cells into mitosis by arresting them in the G(2) phase of the cell cycle. In spite of these intriguing properties, the role of this protein in the life cycle of the virus is not clear. Here we report that after binding to and collapsing the cytokeratin network, the HPV type 16 E1 empty set E4 protein binds to mitochondria. When cytokeratin is not present in the cell, E1 empty set E4 appears associated with mitochondria soon after its synthesis. The leucine cluster within the N-terminal portion of the E1 empty set E4 protein is pivotal in mediating this association. After the initial binding to mitochondria, the E1 empty set E4 protein induces the detachment of mitochondria from microtubules, causing the organelles to form a single large cluster adjacent to the nucleus. This is followed by a severe reduction in the mitochondrial membrane potential and an induction of apoptosis. HPV DNA replication and virion production occur in terminally differentiating cells which are keratin-rich, rigid squamae that exfoliate after completion of the differentiation process. Perturbation of the cytokeratin network and the eventual induction of apoptotic properties are processes that could render these unyielding cells more fragile and ease the exit of newly synthesized HPVs for subsequent rounds of infection.
Insights
The human papillomavirus (HPV) E1^E4 protein disrupts cell structure by targeting cytokeratin and mitochondria. This leads to apoptosis, potentially aiding HPV
Area of Science:
- Virology
- Cell Biology
- Molecular Biology
Background:
- The human papillomavirus (HPV) E1^E4 protein is highly expressed in infected cells.
- It interacts with cytokeratins and DEAD-box proteins, and can arrest cells in G2 phase.
- Its precise role in the HPV life cycle remains unclear.
Purpose of the Study:
- To elucidate the function of the HPV E1^E4 protein in the viral life cycle.
- To investigate the interactions of E1^E4 with cellular components, particularly mitochondria.
- To understand how E1^E4 influences cellular processes relevant to viral replication and release.
Main Methods:
- Investigating the binding of HPV type 16 E1^E4 to cytokeratin and mitochondria in epithelial cells.
- Analyzing the role of the N-terminal leucine cluster in E1^E4-mitochondria association.
- Assessing the impact of E1^E4 on mitochondrial membrane potential and apoptosis induction.
- Correlating cellular changes induced by E1^E4 with HPV replication and virion production.
Main Results:
- HPV E1^E4 binds to and collapses the cytokeratin network.
- E1^E4 associates with mitochondria, independent of cytokeratin presence.
- A leucine cluster in the N-terminus is crucial for mitochondrial binding.
- E1^E4 causes mitochondrial detachment from microtubules, clustering, reduced membrane potential, and apoptosis.
- These effects may facilitate viral release from terminally differentiating keratinocytes.
Conclusions:
- The HPV E1^E4 protein plays a significant role in manipulating host cell machinery.
- By disrupting cytokeratins and inducing mitochondrial dysfunction and apoptosis, E1^E4 may promote viral spread.
- Understanding E1^E4's functions offers insights into HPV pathogenesis and potential therapeutic targets.
Related Concept Videos
02:33Initiation of Translation
First, the initiator tRNA must be selected from the pool of elongator tRNAs by eukaryotic initiation factor 2 (eIF2). The initiator tRNA (Met-tRNAi) has conserved sequence elements including modified bases at...
01:19Inhibitors of Virion Maturation and Assembly
03:18Non-LTR Retrotransposons
01:19Translocation of Proteins into the Mitochondria
Sorting of outer membrane proteins:
Mitochondrial outer membrane proteins are of two types: the transmembrane, beta-barrel porins, and the membrane-anchored, alpha-helical proteins. Beta-barrel porin precursors are translocated by the TOM complex and inserted into the outer mitochondrial membrane by the SAM complex. In contrast,...
01:37Mitochondria
01:37Mitochondria