Dual agonistic and antagonistic roles of ZC3H18 provide for co-activation of distinct nuclear RNA decay pathways

Patrik Polák, William Garland, Om Rathore, Manfred Schmid, Anna Salerno-Kochan, Lis Jakobsen, Maria Gockert, Piotr Gerlach, Toomas Silla, Jens S. Andersen, Elena Conti, Torben Heick Jensen*

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Abstract

The RNA exosome is a versatile ribonuclease. In the nucleoplasm of mammalian cells, it is assisted by its adaptors the nuclear exosome targeting (NEXT) complex and the poly(A) exosome targeting (PAXT) connection. Via its association with the ARS2 and ZC3H18 proteins, NEXT/exosome is recruited to capped and short unadenylated transcripts. Conversely, PAXT/exosome is considered to target longer and adenylated substrates via their poly(A) tails. Here, mutational analysis of the core PAXT component ZFC3H1 uncovers a separate branch of the PAXT pathway, which targets short adenylated RNAs and relies on a direct ARS2-ZFC3H1 interaction. We further demonstrate that similar acidic-rich short linear motifs of ZFC3H1 and ZC3H18 compete for a common ARS2 epitope. Consequently, while promoting NEXT function, ZC3H18 antagonizes PAXT activity. We suggest that this organization of RNA decay complexes provides co-activation of NEXT and PAXT at loci with abundant production of short exosome substrates.

OriginalsprogEngelsk
Artikelnummer113325
TidsskriftCell Reports
Vol/bind42
Udgave nummer11
Antal sider21
ISSN2211-1247
DOI
StatusUdgivet - 28. nov. 2023

Bibliografisk note

Funding Information:
We thank Nadia L. Schmidt and Dorthe C. Riishøj for invaluable technical assistance. John LaCava (Rockefeller University) is thanked for sharing anti-GFP llama polyclonal antibodies. Work in the T.H.J. laboratory was supported by the Danish National Research Council , the Lundbeck Foundation , and the Novo Nordisk Foundation (NNF) (ExoAdapt grant 31199 ), the latter of which also supported the collaborative work in the laboratories of E.C. and J.S.A. Work in the E.C. laboratory was further supported by funding from the Max Planck Society , the European Research Council (EXORICO ERC Advanced Grant 740329 ), and the German Research Foundation ( DFG SFB 1035 , GRK 1721 , SFB/TRR 237 ).

Funding Information:
We thank Nadia L. Schmidt and Dorthe C. Riishøj for invaluable technical assistance. John LaCava (Rockefeller University) is thanked for sharing anti-GFP llama polyclonal antibodies. Work in the T.H.J. laboratory was supported by the Danish National Research Council, the Lundbeck Foundation, and the Novo Nordisk Foundation (NNF) (ExoAdapt grant 31199), the latter of which also supported the collaborative work in the laboratories of E.C. and J.S.A. Work in the E.C. laboratory was further supported by funding from the Max Planck Society, the European Research Council (EXORICO ERC Advanced Grant 740329), and the German Research Foundation (DFG SFB 1035, GRK 1721, SFB/TRR 237). P.P. W.G. T.S. and T.H.J. conceived the project. P.P. and W.G. performed most experiments and cell line generation. M.S. carried out all computational analysis of RNA-seq data. M.G. performed the analysis of 3′-end RNA-seq data. A.S.-K. and P.G. designed and performed all in vitro experiments. L.J. performed the mass spectrometry experiments and raw data processing. P.P. performed the analysis of processed MS data. O.R. contributed to IP experiments. T.H.J. E.C. and J.S.A. supervised the project. P.P. W.G. and T.H.J. wrote the manuscript with input from all co-authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research.

Publisher Copyright:
© 2023 The Author(s)

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