A mutation in POLR3E impairs antiviral immune response and RNA polymerase III

Aravind Ramanathan, Michael Weintraub, Natalie Orlovetskie, Raphael Serruya, Dhivakar Mani, Orly Marcu, Polina Stepensky, Yiska Weisblum, Esther Djian, Avraham Shaag, Shoshana Revel-Vilk, Iris Fried, Moshe Kotler, Alex Rouvinski, Dana Wolf, Orly Elpeleg, Nayef Jarrous

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


RNA polymerase (Pol) III has a noncanonical role of viral DNA sensing in the innate immune system. This polymerase transcribes viral genomes to produce RNAs that lead to induction of type I interferons (IFNs). However, the genetic and functional links of Pol III to innate immunity in humans remain largely unknown. Here, we describe a rare homozygous mutation (D40H) in the POLR3E gene, coding for a protein subunit of Pol III, in a child with recurrent and systemic viral infections and Langerhans cell histiocytosis. Fibroblasts derived from the patient exhibit impaired induction of type I IFN and increased susceptibility to human cytomegalovirus (HCMV) infection. Cultured cell lines infected with HCMV show induction of POLR3E expression. However, induction is not restricted to DNA virus, as sindbis virus, an RNA virus, enhances the expression of this protein. Likewise, foreign nonviral DNA elevates the steady-state level of POLR3E and elicits promoter-dependent and -independent transcription by Pol III. Remarkably, the molecular mechanism underlying the D40H mutation of POLR3E involves the assembly of defective initiation complexes of Pol III. Our study links mutated POLR3E and Pol III to an innate immune deficiency state in humans.

Original languageAmerican English
Pages (from-to)22113-22121
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number36
StatePublished - 8 Sep 2020

Bibliographical note

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  • Cytomegalovirus
  • Innate immunity
  • POLR3E
  • RNA polymerase III
  • Transcription


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