Site-specific proteasome phosphorylation controls cell proliferation and tumorigenesis

Despite the fundamental importance of proteasomal degradation in cells, little is known about whether and how the 26S proteasome itself is regulated in coordination with various physiological processes. Here we show that the proteasome is dynamically phosphorylated during the cell cycle at Thr 25 of the 19S subunit Rpt3. CRISPR/Cas9-mediated genome editing, RNA interference and biochemical studies demonstrate that blocking Rpt3-Thr25 phosphorylation markedly impairs proteasome activity and impedes cell proliferation. Through a kinome-wide screen, we have identified dual-specificity tyrosine-regulated kinase 2 (DYRK2) as the primary kinase that phosphorylates Rpt3-Thr25, leading to enhanced substrate translocation and degradation. Importantly, loss of the single phosphorylation of Rpt3-Thr25 or knockout of DYRK2 significantly inhibits tumour formation by proteasome-addicted human breast cancer cells in mice. These findings define an important mechanism for proteasome regulation and demonstrate the biological significance of proteasome phosphorylation in regulating cell proliferation and tumorigenesis

Proteostasis in cardiac health and disease

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin-proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting