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Cell. 2018 Jun 28;174(1):187-201.e12. doi: 10.1016/j.cell.2018.04.017. Epub 2018 May 17.

PNPT1 Release from Mitochondria during Apoptosis Triggers Decay of Poly(A) RNAs.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu.

Abstract

Widespread mRNA decay, an unappreciated feature of apoptosis, enhances cell death and depends on mitochondrial outer membrane permeabilization (MOMP), TUTases, and DIS3L2. Which RNAs are decayed and the decay-initiating event are unknown. Here, we show extensive decay of mRNAs and poly(A) noncoding (nc)RNAs at the 3' end, triggered by the mitochondrial intermembrane space 3'-to-5' exoribonuclease PNPT1, released during MOMP. PNPT1 knockdown inhibits apoptotic RNA decay and reduces apoptosis, while ectopic expression of PNPT1, but not an RNase-deficient mutant, increases RNA decay and cell death. The 3' end of PNPT1 substrates thread through a narrow channel. Many non-poly(A) ncRNAs contain 3'-secondary structures or bind proteins that may block PNPT1 activity. Indeed, mutations that disrupt the 3'-stem-loop of a decay-resistant ncRNA render the transcript susceptible, while adding a 3'-stem-loop to an mRNA prevents its decay. Thus, PNPT1 release from mitochondria during MOMP initiates apoptotic decay of RNAs lacking 3'-structures.

KEYWORDS:

DIS3L2; PABPC1; PNPT1; RNA decay; RNase; TUTase; apoptosis; caspase; mitochondrial outer membrane permeabilization

PMID:
29779946
DOI:
10.1016/j.cell.2018.04.017

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