Phosphomimicry on STAU1 Serine 20 Impairs STAU1 Posttranscriptional Functions and Induces Apoptosis in Human Transformed Cells

Abstract

Staufen 1 (STAU1) is an RNA-binding protein that is essential in untransformed cells. In cancer cells, it is rather STAU1 overexpression that impairs cell proliferation. In this paper, we show that a modest increase in STAU1 expression in cancer cells triggers apoptosis as early as 12 h post-transfection and impairs proliferation in non-apoptotic cells for several days. Interestingly, a mutation that mimics the phosphorylation of STAU1 serine 20 is sufficient to cause these phenotypes, indicating that serine 20 is at the heart of the molecular mechanism leading to apoptosis. Mechanistically, phosphomimicry on serine 20 alters the ability of STAU1 to regulate translation and the decay of STAU1-bound mRNAs, indicating that the posttranscriptional regulation of mRNAs by STAU1 controls the balance between proliferation and apoptosis. Unexpectedly, the expression of RBD2S20D, the N-terminal 88 amino acids with no RNA-binding activity, is sufficient to induce apoptosis via alteration, in trans, of the posttranscriptional functions of endogenous STAU1. These results suggest that STAU1 is a sensor that controls the balance between cell proliferation and apoptosis, and, therefore, may be considered as a novel therapeutic target against cancer.

A Degradation Motif in STAU1 Defines a Novel Family of Proteins Involved in Inflammation

“…STAU1 55 expression is essential in untransformed cells as it facilitates checkpoint transition [ 29 ]. STAU1 55 is involved in multiple pathways that control development, differentiation, stress granule regulation, synaptic plasticity and long-term potentiation, apoptosis, cell proliferation, RNA virus replication, and immune response to virus infection [ 23 , 30 , 31 , 32 , 33 ]. It is also clearly linked to cancer development, cell migration, metastasis, and tumor angiogenesis [ 23 ].…”

“…It is also clearly linked to cancer development, cell migration, metastasis, and tumor angiogenesis [ 23 ]. In cancer cells, STAU1 55 overexpression impairs cell proliferation and induces apoptosis [ 19 , 33 ]. Interestingly, recent studies link STAU1 55 to proinflammatory processes [ 32 , 34 ].…”