TNIP2 inhibits amyloidogenesis by regulating the 3′UTR of BACE1: An in vitro study

TNFAIP3-interacting protein 2 (TNIP2) is known as a negative regulator of NF-kappa B signaling and inhibit inflammatory response and apoptosis, and is also involved in RNA metabolism. In this study, we investigated the potential role of TNIP2 in amyloidogenesis critically associated with Alzheimer's disease (AD). We found a significant decline of TNIP2 protein level in both mouse and cell model of AD. In SH-SY5Y and HEK cells that stably express human full-length APP695 (SY5Y-APP and HEK-APP), TNIP2 overexpression decreased the protein levels of beta-secretase (BACE1) and C99, as well as A beta peptides (including A beta 40 and A beta 42), while those of alpha-secretase (ADAM10) and the related C83 remained unchanged. We further found that TNIP2 promoted the degradation of BACE1 mRNA and was able to bound to the 3' untranslated region (3' UTR) with the reduced luciferase activity. These results indicated that TNIP2 effectively inhibited amyloidogenic processing by regulating the 3' UTR-associated mRNA decay of BACE1.

Automated summary

TNIP2 plays a crucial role in amyloidogenesis associated with Alzheimer's disease (AD). This study reveals that TNIP2 protein level is significantly decreased in AD models. Overexpression of TNIP2 reduces the protein levels of BACE1 and C99, as well as Aβ peptides, and inhibits amyloidogenesis. TNIP2 promotes the degradation of BACE1 mRNA by binding to its 3' UTR, leading to the inhibition of amyloidogenic processing.