The polymerized protein response (PPR) is activated by genetic variants that polymerize in the ER and is mediated by NFκBp50

In previous studies we have shown that accumulation of the polymerogenic variant ATZ that causes α1-antitrypsin deficiency (ATD) activates NFκB DNA binding. Here we discovered that this response, which we are naming the polymerized protein response (PPR), is characterized by NFκB p50 homodimers, distinct from the p50/p65 heterodimers in the canonical NFκB inflammatory response and the unfolded protein response (UPR). The PPR is also activated by other disease associated variants that polymerize in the ER whereas disease-associated variants that do not form polymers activate p50/p65 heterodimers and UPR. The PPR elicits a unique gene expression profile, including changes that stabilize p50 homodimers in cytoplasm and nucleus. The PPR is blocked by specific genetic substitutions within the luminal and cytosolic domains of Derlin-2 providing evidence that the ERAD retrotranslocation complex is a proximal transducer of this signaling mechanism. We hypothesize that the PPR is a proteostasis response pathway complementary to the UPR, designed to protect the cell from the specific proteotoxic effects of polymers that form aberrantly in the ER.