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

Publisher: Macmillan Magazines Ltd Country of Publication: England NLM ID: 100890575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4679 (Electronic) Linking ISSN: 14657392 NLM ISO Abbreviation: Nat Cell Biol Subsets: MEDLINE

Original Publication: London : Macmillan Magazines Ltd., [1999-

Endoplasmic Reticulum/*metabolism ; Endoribonucleases/*metabolism ; Poly(ADP-ribose) Polymerases/*metabolism ; Protein Serine-Threonine Kinases/*metabolism ; Unfolded Protein Response/*physiology ; eIF-2 Kinase/*metabolism; Endoplasmic Reticulum Stress/genetics ; Endoplasmic Reticulum Stress/physiology ; Endoribonucleases/genetics ; HeLa Cells ; Humans ; Poly(ADP-ribose) Polymerases/genetics ; Protein Serine-Threonine Kinases/genetics ; Reactive Oxygen Species/metabolism ; Unfolded Protein Response/genetics ; eIF-2 Kinase/genetics

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  , , ). PARPs regulate key stress response pathways, including DNA damage repair and the cytoplasmic stress response. 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.

Erratum in: Nat Cell Biol. 2013 Jan;15(1):123.

Semin Cell Dev Biol. 2007 Dec;18(6):716-31. (PMID: 18023214)
Nat Rev Mol Cell Biol. 2006 Jul;7(7):517-28. (PMID: 16829982)
Cell. 2008 Aug 22;134(4):634-45. (PMID: 18724936)
Nat Methods. 2006 Mar;3(3):205-10. (PMID: 16489338)
Front Biosci. 2008 Jan 01;13:3046-82. (PMID: 17981777)
Curr Opin Cell Biol. 2007 Aug;19(4):368-75. (PMID: 17629691)
J Cell Biol. 2004 Oct 11;167(1):35-41. (PMID: 15466483)
Biochem Cell Biol. 2005 Jun;83(3):354-64. (PMID: 15959561)
Mol Cell. 2008 Oct 10;32(1):57-69. (PMID: 18851833)
J Mol Biol. 1989 Nov 5;210(1):229-33. (PMID: 2511329)
Annu Rev Cell Dev Biol. 2002;18:575-99. (PMID: 12142265)
Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29. (PMID: 17565364)
Trends Biochem Sci. 2010 Apr;35(4):208-19. (PMID: 20106667)
Mol Cell. 2011 May 20;42(4):489-99. (PMID: 21596313)
Curr Opin Cell Biol. 2011 Apr;23(2):135-42. (PMID: 21093243)
J Biol Chem. 1996 Mar 29;271(13):7583-6. (PMID: 8631791)
Nat Cell Biol. 2000 Jun;2(6):326-32. (PMID: 10854322)
Nat Rev Drug Discov. 2008 Dec;7(12):1013-30. (PMID: 19043451)
Science. 2011 Nov 25;334(6059):1081-6. (PMID: 22116877)
Cell. 1997 May 16;89(4):535-44. (PMID: 9160745)
Methods Mol Biol. 2008;419:197-214. (PMID: 18369985)

P30 CA014051 United States CA NCI NIH HHS; R01 GM087465 United States GM NIGMS NIH HHS; P30-CA14051 United States CA NCI NIH HHS; 5R01GM087465-02 United States GM NIGMS NIH HHS

0 (Reactive Oxygen Species)
EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
EC 2.7.11.1 (ERN1 protein, human)
EC 2.7.11.1 (PERK kinase)
EC 2.7.11.1 (Protein Serine-Threonine Kinases)
EC 2.7.11.1 (eIF-2 Kinase)
EC 3.1.- (Endoribonucleases)

Date Created: 20121030 Date Completed: 20130116 Latest Revision: 20211203

20221213

PMC3494284

10.1038/ncb2593

23103912