Format

Send to

Choose Destination
EMBO Rep. 2019 Dec 23:e48073. doi: 10.15252/embr.201948073. [Epub ahead of print]

HOPS/TMUB1 retains p53 in the cytoplasm and sustains p53-dependent mitochondrial apoptosis.

Author information

1
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
2
Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, Perugia, Italy.
3
Unit of Cellular Networks and Molecular Therapeutic Targets, IRCCS - Regina Elena National Cancer Institute, Rome, Italy.

Abstract

Apoptotic signalling by p53 occurs at both transcriptional and non-transcriptional levels, as p53 may act as a direct apoptogenic stimulus via activation of the intrinsic mitochondrial pathway. HOPS is a highly conserved, ubiquitously expressed shuttling protein with an ubiquitin-like domain. We generated Hops-/- mice and observed that they are viable with no apparent phenotypic defects. However, when treated with chemotherapeutic agents, Hops-/- mice display a significant reduction in apoptosis, suggesting an impaired ability to respond to genotoxic stressors. We show that HOPS acts as a regulator of cytoplasmic p53 levels and function. By binding p53, HOPS inhibits p53 proteasomal degradation and favours p53 recruitment to mitochondria and apoptosis induction. By interfering with importin α, HOPS further increases p53 cytoplasmic levels. Thus, HOPS promotes the p53-dependent mitochondrial apoptosis pathway by preserving cytoplasmic p53 from both degradation and nuclear uptake.

KEYWORDS:

HOPS ; TMUB1; apoptosis; mitochondria; p53; ubiquitin like

PMID:
31867855
DOI:
10.15252/embr.201948073

Supplemental Content

Full text links

Icon for Wiley
Loading ...
Support Center