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PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response

Nature Cell Biology volume 14, pages 1223–1230 (2012)Cite this article

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A Corrigendum to this article was published on 24 December 2012

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Abstract

Poly(ADP-ribose) polymerases (PARPs; also known as ADP-ribosyl transferase D proteins) modify acceptor proteins with ADP-ribose modifications of varying length (reviewed in refs 1, 2, 3). PARPs regulate key stress response pathways, including DNA damage repair and the cytoplasmic stress response2,3,4,5,6. Here, we show that PARPs also regulate the unfolded protein response (UPR) of the endoplasmic reticulum (ER). Human PARP16 (also known as ARTD15) is a tail-anchored ER transmembrane protein required for activation of the functionally related ER stress sensors PERK and IRE1α during the UPR. The third identified ER stress sensor, ATF6, is not regulated by PARP16. As is the case for other PARPs that function during stress, the enzymatic activity of PARP16 is upregulated during ER stress when it ADP-ribosylates itself, PERK and IRE1α. ADP-ribosylation by PARP16 is sufficient for activating PERK and IRE1α in the absence of ER stress, and is required for PERK and IRE1α activation during the UPR. Modification of PERK and IRE1α by PARP16 increases their kinase activities and the endonuclease activity of IRE1α. Interestingly, the carboxy-terminal luminal tail of PARP16 is required for PARP16 function during ER stress, suggesting that it transduces stress signals to the cytoplasmic PARP catalytic domain.

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Figure 1: PARP16 is a tail-anchored ER transmembrane protein.
Figure 2: ADP-ribosylation activity of PARP16 is required for the ER stress response.
Figure 3: PERK and IRE1α are ADP-ribosylated in a PARP16-dependent manner during the UPR.
Figure 4: Enzymatic activity of PARP16 is required for activation of PERK- and IRE1α-mediated UPR.
Figure 5: The C-tail of PARP16 is required for activation of PERK- and IRE1α-mediated UPR.

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  • 19 November 2012

    the version of this Letter initially published online and in print, the reference (PLoS ONE 7, e37352; 2012) was inadvertently omitted from the reference list.

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Acknowledgements

We thank N. Borgese (University of Milan, Italy) for sharing reagents; T. Sangpo for technical assistance; and T. Jacks, H. Lodish, H. Ploegh, U. L. RajBhandary and M. Chesarone-Cataldo for comments on the manuscript. P.C. is a Rita Allen Foundation Scholar, a Kimmel Foundation for Cancer Research Scholar, and was a Howard S. and Linda B. Stern Career Development assistant professor. This work is partially financially supported by Cancer Center Support (core grant P30-CA14051), grant 5R01GM087465-02 from the National Institutes of Health (P.C.), Curt and Kathy Marble, the Jeptha H. and Emily V. Wade Fund (P.C.) and the Ludwig fund for Cancer Research fellowship (M.J.).

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Authors and Affiliations

  1. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    Miri Jwa & Paul Chang

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    Paul Chang

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  1. Miri Jwa
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P.C. and M.J. designed the experiments and wrote the manuscript. M.J. performed the experiments and data analysis.

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Correspondence to Paul Chang.

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Jwa, M., Chang, P. PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response. Nat Cell Biol 14, 1223–1230 (2012). https://doi.org/10.1038/ncb2593

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