Activity and Function in Human Cells of the Evolutionary Conserved Exonuclease Polynucleotide Phosphorylase

Abstract

Polynucleotide phosphorylase (PNPase) is a phosphorolytic RNA exonuclease highly conserved throughout evolution. Human PNPase (hPNPase) is located in mitochondria and is essential for mitochondrial function and homeostasis. Not surprisingly, mutations in the PNPT1 gene, encoding hPNPase, cause serious diseases. hPNPase has been implicated in a plethora of processes taking place in different cell compartments and involving other proteins, some of which physically interact with hPNPase. This paper reviews hPNPase RNA binding and catalytic activity in relation with the protein structure and in comparison, with the activity of bacterial PNPases. The functions ascribed to hPNPase in different cell compartments are discussed, highlighting the gaps that still need to be filled to understand the physiological role of this ancient protein in human cells.

Keywords: PNPT1; PNPase; RNA binding protein; RNA decay; RNA degradosome; RNA stability; exoribonuclease; mitochondrial RNA; polyribonucleotide phosphorylase.

Figure 1

PNPT1 transcription induction by type I interferon. IFN-β and INF-α (IFN) induce the JAK-STAT signaling cascade described in the text leading to PNPT1 transcription activation by ISGF3. STAT2/IRF9 complex, which could also bind the ISRE, is not shown. Created with Biorender.com. Available online: https://biorender.com (accessed on 27 January 2022).

Figure 2

Structure of hPNPase. (a) Domain organization. The boxes represent the five evolutionarily conserved motifs that include MLS, mitochondrial localization sequence; AAHD, All α-helical domain; RPH1, Ribonuclease PH domain 1; RPH2, Ribonuclease PH domain 2; KH, K homology domain; S1, S1 domain. N, N-terminus; C, C-terminus. Created with Biorender.com. Available online: https://biorender.com/ (accessed on 27 January 2022). (b) Structure of monomeric (left) and trimeric (central, side view, and right, top view) truncated (devoid of S1 domain) hPNPase (PDB ID: 3U1K). The domains are colored as in panel a.

Figure 3

hPNPase mitochondrial functions. RNA to be imported may cross the mt outer membrane through the TOM translocon. hPNPase in the IMS facilitates RNA transport to the matrix with an unclear mechanism. In the matrix, the mtDEG regulates the decay and the polyadenylation of mtRNA, the degradation of dsRNA, and the processing of R-loops. Created with Biorender.com. Available online: https://biorender.com/ (accessed on 27 January 2022).