PARP16

PARP16 is a tail-anchored endoplasmic reticulum (ER) mono-ADP-ribosyltransferase that functions as a key regulator of cellular stress signaling through protein ADP-ribosylation^[1]. Mechanistically, PARP16 promotes activation of the unfolded protein response (UPR) by ADP-ribosylating the ER stress sensors PERK (EIF2AK3) and IRE1α (ERN1), thereby enhancing downstream ER stress signaling and maintaining proteostasis under conditions of protein-folding stress^[1]. PARP16 enzymatic activity increases during ER stress, and its ADP-ribosylation activity is both necessary and sufficient for efficient PERK and IRE1α activation, establishing PARP16 as an upstream regulator of the UPR pathway^[1]. Beyond stress sensing, PARP16 participates in translational control through mono-ADP-ribosylation of ribosomal proteins, linking ER homeostasis to regulation of protein synthesis^[2][3]. In disease-relevant models, elevated PARP16 activity enhances ER stress signaling and contributes to pathological cellular responses, whereas PARP16 depletion suppresses UPR activation and reduces disease-associated phenotypes^[4][5]. For example, PARP16 knockdown attenuates ER stress-mediated neuronal injury in ischemia/reperfusion-related models, supporting a functional role in stress-induced cell death pathways^[5]. Compared with nuclear DNA damage-responsive PARP family members such as PARP1, PARP16 is distinguished by its ER membrane localization and selective regulation of PERK- and IRE1α-dependent UPR signaling rather than canonical DNA repair mechanisms^[1]. Therefore, PARP16 represents a valuable experimental target for investigating ER stress biology, UPR regulation, and diseases driven by chronic proteotoxic stress^[1][4][5].