Lamin B receptor plays a key role in cellular senescence induced by inhibition of the proteasome.

Cellular senescence is a terminal growth arrest phenomenon in mammalian cells. Coordinated regulation of protein synthesis and degradation is required to maintain protein homeostasis in cells; however, senescent cells exhibit decreased activity of the proteasome, a major cellular proteolytic machinery, with an accumulation of proteins. Indeed, we showed that MG132, a proteasome inhibitor, induced cellular senescence through an accumulation of proteins in human cells. We then investigated the mechanisms of cellular senescence induced by protein accumulation by treating cells with MG132. We found that lamin B receptor (LBR), a nuclear membrane protein that regulates heterochromatin organization, was mislocalized and down-regulated in cells on treatment with MG132. Importantly, enforced expression of LBR suppressed cellular senescence induced by MG132. We also showed that LBR was involved in the regulation of chromatin organization in senescent cells, and that endoplasmic reticulum stress and autophagy were likely to be involved in the mislocalization and down-regulation of LBR. These findings indicate that decreased LBR function was responsible for the induction of cellular senescence by MG132, and thus suggest that protein accumulation caused by inhibition of the proteasome induced cellular senescence probably through chromatin dysregulation in human cells.

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© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.