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

doi:10.1016/j.celrep.2023.113325

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^*

^*Corresponding author af dette arbejde

Institut for Molekylærbiologi og Genetik - RNA-biologi og -innovation

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

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.

Originalsprog	Engelsk
Artikelnummer	113325
Tidsskrift	Cell Reports
Vol/bind	42
Nummer	11
ISSN	2211-1247
DOI	https://doi.org/10.1016/j.celrep.2023.113325
Status	Udgivet - nov. 2023

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10.1016/j.celrep.2023.113325

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@article{373262637cb348319a030620e7a9b097,

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

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.",

keywords = "activation, ARS2, CP: Molecular biology, inhibition, NEXT, nuclear RNA decay, PAXT, ZC3H18",

author = "Patrik Pol{\'a}k and William Garland and Om Rathore and Manfred Schmid and Anna Salerno-Kochan and Lis Jakobsen and Maria Gockert and Piotr Gerlach and Toomas Silla and Andersen, {Jens S.} and Elena Conti and Jensen, {Torben Heick}",

year = "2023",

month = nov,

doi = "10.1016/j.celrep.2023.113325",

language = "English",

volume = "42",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - Dual agonistic and antagonistic roles of ZC3H18 provide for co-activation of distinct nuclear RNA decay pathways

AU - Polák, Patrik

AU - Garland, William

AU - Rathore, Om

AU - Schmid, Manfred

AU - Salerno-Kochan, Anna

AU - Jakobsen, Lis

AU - Gockert, Maria

AU - Gerlach, Piotr

AU - Silla, Toomas

AU - Andersen, Jens S.

AU - Conti, Elena

AU - Jensen, Torben Heick

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

KW - activation

KW - ARS2

KW - CP: Molecular biology

KW - inhibition

KW - NEXT

KW - nuclear RNA decay

KW - PAXT

KW - ZC3H18

U2 - 10.1016/j.celrep.2023.113325

DO - 10.1016/j.celrep.2023.113325

M3 - Journal article

C2 - 37889751

AN - SCOPUS:85174817594

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 11

M1 - 113325

ER -

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

Abstract

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