GTF3A mutations predispose to herpes simplex encephalitis by disrupting biogenesis of the host-derived RIG-I ligand RNA5SP141

Leslie Naesens, Santoshi Muppala, Dhiraj Acharya, Josephine Nemegeer, Delfien Bogaert, Jung Hyun Lee, Katrien Staes, Veronique Debacker, Pieter De Bleser, Marieke De Bruyne, Elfride De Baere, Michiel van Gent, Guan Qun Liu, Bart N. Lambrecht, Jens Staal, Tessa Kerre, Rudi Beyaert, Jonathan Maelfait, Simon J. Tavernier, Michaela U. Gack*Filomeen Haerynck*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)


Herpes simplex virus 1 (HSV-1) infects several billion people worldwide and can cause life-threatening herpes simplex encephalitis (HSE) in some patients. Monogenic defects in components of the type I interferon system have been identified in patients with HSE, emphasizing the role of inborn errors of immunity underlying HSE pathogenesis. Here, we identify compound heterozygous loss-of-function mutations in the gene GTF3A encoding for transcription factor IIIA (TFIIIA), a component of the RNA polymerase III complex, in a patient with common variable immunodeficiency and HSE. Patient fibroblasts and GTF3A gene–edited cells displayed impaired HSV-1–induced innate immune responses and enhanced HSV-1 replication. Chromatin immunoprecipitation sequencing analysis identified the 5S ribosomal RNA pseudogene 141 (RNA5SP141), an endogenous ligand of the RNA sensor RIG-I, as a transcriptional target of TFIIIA. GTF3A mutant cells exhibited diminished RNA5SP141 expression and abrogated RIG-I activation upon HSV-1 infection. Our work unveils a crucial role for TFIIIA in transcriptional regulation of a cellular RIG-I agonist and shows that GTF3A genetic defects lead to impaired cell-intrinsic anti–HSV-1 responses and can predispose to HSE.

Original languageEnglish
Article numbereabq4531
JournalScience immunology
Issue number77
Publication statusPublished - Nov 2022
Externally publishedYes

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