Oxidative Stress Causes Enhanced Secretion of YB-1 Protein that Restrains Proliferation of Receiving Cells

Abstract

The prototype cold-shock Y-box binding protein 1 (YB-1) is a multifunctional protein that regulates a variety of fundamental biological processes including cell proliferation and migration, DNA damage, matrix protein synthesis and chemotaxis. The plethora of functions assigned to YB-1 is strictly dependent on its subcellular localization. In resting cells, YB-1 localizes to cytoplasm where it is a component of messenger ribonucleoprotein particles. Under stress conditions, YB-1 contributes to the formation of stress granules (SGs), cytoplasmic foci where untranslated messenger RNAs (mRNAs) are sorted or processed for reinitiation, degradation, or packaging into ribonucleoprotein particles (mRNPs). Following DNA damage, YB-1 translocates to the nucleus and participates in DNA repair thereby enhancing cell survival. Recent data show that YB-1 can also be secreted and YB-1-derived polypeptides are found in plasma of patients with sepsis and malignancies. Here we show that in response to oxidative insults, YB-1 assembly in SGs is associated with an enhancement of YB-1 protein secretion. An enriched fraction of extracellular YB-1 (exYB-1) significantly inhibited proliferation of receiving cells and such inhibition was associated to a G2/M cell cycle arrest, induction of p21WAF and reduction of ΔNp63α protein level. All together, these data show that acute oxidative stress causes sustained release of YB-1 as a paracrine/autocrine signal that stimulate cell cycle arrest.

The ArathEULS3 Lectin Ends up in Stress Granules and Can Follow an Unconventional Route for Secretion

“…Similar to ArathEULS3, the secretion of hygromycin phosphatase and mannitol dehydrogenase was not mediated by any vesicular structures [45,46]. Interestingly, the mammalian Y-box protein YB-1 assembly in stress granules was recently associated with an enhancement of its unconventional secretion [47]. The YB-1 protein is involved in many fundamental biological processes and its localization highly depends on the conditions.…”

Y-Box Binding Proteins in mRNP Assembly, Translation, and Stability Control

“…PABPC1 is a shuttle protein with predominantly cytoplasmic localization that binds to mRNA after its export from the nucleus [112]. Recently, it was found that PABPC1 accumulates in the nucleus upon YB-1 knockdown [113]. We speculate that YB-1 creates not only competitive conditions favorable for PABP functioning but also assists mRNP rearrangement in the nuclear pore.…”

“…In the majority of YB-1 secretion studies, the intracellular YB-1 level was not measured [198][199][200]. Only one study reports that under oxidative stress caused by sodium arsenite or H 2 O 2 treatment, YB-1 can secrete from the cell, and its intracellular concentration is slightly decreased [113]. Changes in the intracellular YB-1 content under oxidative stress and other stimuli are subject to further detailed investigation.…”

Critical role for cold shock protein YB-1 in cytokinesis

“…and cyclin E 19 . In contrast, a role for an N-terminal 77 amino acid domain of YB-1 has been implicated in regulating progression of the G2/M phases of the cell cycle 20 and other studies have demonstrated that inhibiting YB-1 caused an arrest at G2/M 21,22 . Furthermore, prolonged exposure of breast cancer cells to YB-1 led to cytokinesis failure and slippage through the G1/S border 23 .…”