PARP16

PARP16 (ARTD15) is a tail-anchored, ER- and nuclear-envelope-resident mono-ADP-ribosyltransferase whose catalytic domain faces the cytosol and acts as a node linking the secretory pathway to the unfolded protein response (PMID:23103912, PMID:22701565). Its crystal structure reveals a transferase domain capped by a novel α-helical domain, and it carries out auto-mono-ADP-ribosylation that is blocked by canonical PARP inhibitors (PMID:22661712). Mechanistically, PARP16 ADP-ribosylates the UPR transducers PERK and IRE1α, and this modification is sufficient to activate their kinase and endonuclease activities even without ER stress, with the C-terminal luminal tail required to relay the stress signal to the cytosolic catalytic domain while ATF6 is left unaffected (PMID:23103912). PARP16 additionally MARylates karyopherin-β1, a nuclear-trafficking component identified as a direct binding partner and substrate (PMID:22701565), and MARylates ribosomal proteins in an NAD+-dependent manner (NAD+ supplied by NMNAT-2) to restrain global protein synthesis and maintain proteostasis, with loss of activity increasing translation and protein aggregation and impairing tumor growth (PMID:41959139). PARP16 catalytic activity also governs its own behavior, sequestering the enzyme into a detergent-insoluble fraction under amino-acid starvation (PMID:36544740). Across vascular and neuronal disease models, PARP16 transcription is epigenetically controlled — upregulated by SMYD3 via H3K4me3 and by KDM6B via removal of H3K27me3 — driving UPR-dependent phenotypes such as neointimal hyperplasia, endothelial senescence, and Aβ-associated neurotoxicity (PMID:34094832, PMID:33144524, PMID:39603516). PARP16 is pharmacologically tractable through both natural-product inhibitors and a structure-guided covalent inhibitor (DB008) targeting Cys169 in the NAD+ pocket (PMID:28698806, PMID:36544740).

1. 2012 High

   Established PARP16's identity as a membrane-anchored MARylating enzyme and its core mechanism: that it ADP-ribosylates PERK and IRE1α to activate the UPR independently of ER stress.

   Evidence Topology/protease protection, in vitro ADP-ribosylation, gain/loss-of-function with kinase/endonuclease readouts, and domain deletion in cells

   PMID:22701565 PMID:23103912

   Open questions at the time

   • How the luminal tail senses ER stress and signals across the membrane is not defined
   • ATF6 arm is excluded but the basis for selectivity is unknown
2. 2012 High

   Provided the structural and biochemical framework, revealing a novel α-helical domain abutting the transferase fold and confirming auto-MARylation sensitive to canonical PARP inhibitors.

   Evidence X-ray crystallography with in vitro auto-ADP-ribosylation and inhibitor assays

   PMID:22661712

   Open questions at the time

   • No substrate-bound or membrane-context structure
   • Function of the α-helical domain not assigned
3. 2017 Medium

   Demonstrated that pharmacological inhibition of PARP16 catalytic activity suppresses PERK phosphorylation and sensitizes cancer cells to ER-stress apoptosis, validating PARP16 as a druggable UPR regulator.

   Evidence In vitro enzyme/binding assays with EGCG plus siRNA knockdown and rescue in cells

   PMID:28698806

   Open questions at the time

   • EGCG is non-selective; off-target contributions not excluded
   • Whether direct PERK MARylation is the inhibited event was not shown
4. 2020 Medium

   Connected PARP16 expression to upstream epigenetic control, showing SMYD3 directly binds the Parp16 promoter and deposits H3K4me3 to drive UPR-dependent vascular pathologies.

   Evidence ChIP/ChIP-seq, knockdown/overexpression, and mouse vascular injury and aging models

   PMID:33144524 PMID:34094832

   Open questions at the time

   • Whether SMYD3 acts directly versus via additional factors not fully resolved
   • Tissue specificity of the SMYD3-PARP16 axis unknown
5. 2020 Low

   Extended PARP16's substrate range into the secretory pathway by positioning it as the priming MARylase for VEGF that licenses subsequent Tankyrase-2 poly-ADP-ribosylation.

   Evidence ADP-ribosylation assays, co-IP, and knockdown

   PMID:32472322

   Open questions at the time

   • Single low-detail report; awaits independent confirmation
   • MARylation site on VEGF and functional consequence not mapped
6. 2020 Medium

   Showed PARP16 is a co-target in disease-relevant pharmacology, with dual PARP3/PARP16 inhibition required to correct F508del-CFTR trafficking.

   Evidence Pull-down, enzyme inhibition, siRNA, and CFTR trafficking assays with selective inhibitor combinations

   PMID:33073085

   Open questions at the time

   • Direct PARP16 substrate in the CFTR pathway not identified
   • Mechanistic link between PARP16 activity and CFTR folding unresolved
7. 2021 Medium

   Identified PARP16 as an unexpected target of the clinical PARP inhibitor talazoparib whose silencing reduces cancer cell survival, broadening its therapeutic relevance.

   Evidence Chemical proteomics, siRNA silencing, viability and combination assays in small cell lung cancer cells

   PMID:34329582

   Open questions at the time

   • Substrate mediating the survival effect not defined
   • Selectivity of talazoparib for PARP16 versus other PARPs incompletely quantified
8. 2022 High

   Delivered a selective covalent chemical tool (DB008) targeting non-conserved Cys169 and uncovered that PARP16 catalytic activity controls its own solubility under nutrient stress.

   Evidence Structure-guided design, Cys169 mutagenesis, click-chemistry in-cell labeling, and cell fractionation under amino-acid starvation

   PMID:36544740

   Open questions at the time

   • Auto-MARylation target sites driving sequestration not mapped
   • Functional purpose of insoluble sequestration unclear
9. 2023 Medium

   Implicated PARP16 in neurodegeneration through two routes: as an RNA-binding protein that stabilizes APP mRNA, and as a UPR driver in ischemic neuronal death.

   Evidence AAV-mediated knockdown and overexpression in mice and primary neurons, RNA-binding/mRNA stability assays, ADP-ribosylation assays, and UPR rescue with Brefeldin A

   PMID:36692424 PMID:37163422

   Open questions at the time

   • RNA-binding activity not reconciled with catalytic MARylation function
   • Whether APP mRNA binding is direct and which domain mediates it not established
10. 2024 Medium

    Identified a second epigenetic activator, KDM6B, which derepresses Parp16 by erasing H3K27me3, with PARP16 acting downstream to mediate Aβ neurotoxicity.

    Evidence ChIP, siRNA and AAV knockdown, and overexpression epistasis rescue in neurons and APP/PS1 mice

    PMID:39603516

    Open questions at the time

    • Interplay between KDM6B and SMYD3 control of the same locus unresolved
    • Direct versus indirect KDM6B recruitment not addressed
11. 2026 High

    Defined a proteostatic role in which NMNAT-2-supplied NAD+ fuels PARP16 auto-MARylation and ribosomal-protein MARylation to restrain translation, with loss promoting aggregation and impairing tumor growth.

    Evidence In vitro reconstitution, CRISPR knockout, drug-resistant mutant rescue, ribosome MARylation MS, polysome profiling, and xenograft (preprint)

    PMID:41959139

    Open questions at the time

    • Preprint not yet peer-reviewed
    • Specific ribosomal protein MARylation sites and their translational consequence not pinpointed

• How PARP16's distinct activities — transmembrane UPR signaling, ribosomal/translational control, RNA binding, and self-solubility regulation — are integrated and selected among its diverse substrates remains unknown.
• No unifying model of substrate selection across UPR sensors, karyopherin-β1, ribosomal proteins, and VEGF
• Physiological signals that switch PARP16 between functions undefined
• No structure of PARP16 engaging any protein substrate