Abstract
The anaphase-promoting complex or cyclosome (APC/C) is a multi-subunit ubiquitin ligase that regulates exit from mitosis and G1 phase of the cell cycle. Although the regulation and function of APC/CCdh1 in the unperturbed cell cycle is well studied, little is known of its role in non-genotoxic stress responses. Here, we demonstrate the role of APC/CCdh1 (APC/C activated by Cdh1 protein) in cellular protection from endoplasmic reticulum (ER) stress. Activation of APC/CCdh1 under ER stress conditions is evidenced by Cdh1-dependent degradation of its substrates. Importantly, the activity of APC/CCdh1 maintains the ER stress checkpoint, as depletion of Cdh1 by RNAi impairs cell cycle arrest and accelerates cell death following ER stress. Our findings identify APC/CCdh1 as a regulator of cell cycle checkpoint and cell survival in response to proteotoxic insults.
Highlights
The anaphase-promoting complex or cyclosome (APC/C) is a multimeric ubiquitin ligase that regulates the progression of mitosis and establishment of G1 in the cell cycle through sequential activation by the substrate-adaptors/activators Cdc20 and Cdh1 [1]
APC/CCdh1 is activated under endoplasmic reticulum (ER) stress conditions When we analyzed the cell cycle response to ER stress in HeLa cells by treatment with tunicamycin (TM), a pharmacological ER stress inducer that inhibits glycosylation of newly synthesized glycoproteins, we observed a marked reduction in the protein levels of endogenous cyclins A and B1, Cdc20, and Polo-like kinase 1 (Plk-1) –all of which are known substrates of the APC/CCdh1 [1] (Figure 1A)
We found that while transcriptional repression likely participated in the reduction of APC/CCdh1 substrates under prolonged TM treatment (Figures 1B-bottom graphs and S1), protein downregulation occurred at a faster rate than transcriptional repression of these substrates, as observed at the early time points following TM treatment (Figures 1A-right panel and 1B)
Summary
The APC/C is a multimeric ubiquitin ligase that regulates the progression of mitosis and establishment of G1 in the cell cycle through sequential activation by the substrate-adaptors/activators Cdc and Cdh1 [1]. Sequential activation of APC/CCdc and APC/CCdh depends on their differential regulation by the mitotic cyclin-dependent kinases (CDKs): CDK-dependent phosphorylation of several subunits of the APC/C core promotes association with Cdc, whereas phosphorylation of Cdh inhibits its binding to the APC/C core [2,3]. This renders APC/CCdc active in mitosis when CDK activities are high and APC/CCdh active in telophase when CDK activities decline. Binding of inhibitors like Emi (early mitotic inhibitor 1) from the G1-S transition to G2 or Rae (RNA export 1 homologue) in early mitosis restricts the activity of the APC/C [5,6,7]
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