scholarly journals p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Ada Nowosad ◽  
Justine Creff ◽  
Pauline Jeannot ◽  
Raphael Culerrier ◽  
Patrice Codogno ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Vesicle Trafficking ◽  
Metabolic Stress ◽  
Glucose Deprivation ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Autophagy Flux ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Autophagy Induction ◽  
Perinuclear Area

AbstractThe cyclin-dependent kinase inhibitor p27Kip1 (p27) has been involved in promoting autophagy and survival in conditions of metabolic stress. While the signaling cascade upstream of p27 leading to its cytoplasmic localization and autophagy induction has been extensively studied, how p27 stimulates the autophagic process remains unclear. Here, we investigated the mechanism by which p27 promotes autophagy upon glucose deprivation. Mouse embryo fibroblasts (MEFs) lacking p27 exhibit a decreased autophagy flux compared to wild-type cells and this is correlated with an abnormal distribution of autophagosomes. Indeed, while autophagosomes are mainly located in the perinuclear area in wild-type cells, they are distributed throughout the cytoplasm in p27-null MEFs. Autophagosome trafficking towards the perinuclear area, where most lysosomes reside, is critical for autophagosome–lysosome fusion and cargo degradation. Vesicle trafficking is mediated by motor proteins, themselves recruited preferentially to acetylated microtubules, and autophagy flux is directly correlated to microtubule acetylation levels. p27−/− MEFs exhibit a marked reduction in microtubule acetylation levels and restoring microtubule acetylation in these cells, either by re-expressing p27 or with deacetylase inhibitors, restores perinuclear positioning of autophagosomes and autophagy flux. Finally, we find that p27 promotes microtubule acetylation by binding to and stabilizing α-tubulin acetyltransferase (ATAT1) in glucose-deprived cells. ATAT1 knockdown results in random distribution of autophagosomes in p27+/+ MEFs and impaired autophagy flux, similar to that observed in p27−/− cells. Overall, in response to glucose starvation, p27 promotes autophagy by facilitating autophagosome trafficking along microtubule tracks by maintaining elevated microtubule acetylation via an ATAT1-dependent mechanism.

scholarly journals A Conserved Gammaherpesvirus Cyclin Specifically Bypasses Host p18INK4cTo Promote Reactivation from Latency

2015 ◽  
Vol 89 (21) ◽  
pp. 10821-10831 ◽  
Author(s):  
Lisa M. Williams ◽  
Brian F. Niemeyer ◽  
David S. Franklin ◽  
Eric T. Clambey ◽  
Linda F. van Dyk
Keyword(s):  
Common Property ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Dependent Manner ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Genetic Ablation ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Viral Cyclin

ABSTRACTGammaherpesviruses (GHVs) carry homologs of cellular genes, including those encoding a viral cyclin that promotes reactivation from latent infection. The viral cyclin has reduced sensitivity to host cyclin-dependent kinase inhibitorsin vitro; however, thein vivosignificance of this is unclear. Here, we tested the genetic requirement for the viral cyclin in mice that lack the host inhibitors p27Kip1and p18INK4c, two cyclin-dependent kinase inhibitors known to be important in regulating B cell proliferation and differentiation. While the viral cyclin was essential for reactivation in wild-type mice, strikingly, it was dispensable for reactivation in mice lacking p27Kip1and p18INK4c. Further analysis revealed that genetic ablation of only p18INK4calleviated the requirement for the viral cyclin for reactivation from latency. p18INK4cregulated reactivation in a dose-dependent manner so that the viral cyclin was dispensable in p18INK4cheterozygous mice. Finally, treatment of wild-type cells with the cytokine BAFF, a known attenuator of p18INK4cfunction in B lymphocytes, was also able to bypass the requirement for the viral cyclin in reactivation. These data show that the gammaherpesvirus viral cyclin functions specifically to bypass the cyclin-dependent kinase inhibitor p18INK4c, revealing an unanticipated specificity between a GHV cyclin and a single cyclin-dependent kinase inhibitor.IMPORTANCEThe gammaherpesviruses (GHVs) cause lifelong infection and can cause chronic inflammatory diseases and cancer, especially in immunosuppressed individuals. Many GHVs encode a conserved viral cyclin that is required for infection and disease. While a common property of the viral cyclins is that they resist inhibition by normal cellular mechanisms, it remains unclear how important it is that the GHVs resist this inhibition. We used a mouse GHV that either contained or lacked a viral cyclin to test whether the viral cyclin lost importance when these inhibitory pathways were removed. These studies revealed that the viral cyclin was required for optimal function in normal mice but that it was no longer required following removal or reduced function of a single cellular inhibitor. These data define a very specific role for the viral cyclin in bypassing one cellular inhibitor and point to new methods to intervene with viral cyclins.

scholarly journals The AMPK/p27Kip1 Pathway as a Novel Target to Promote Autophagy and Resilience in Aged Cells

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1430
Author(s):  
Lauren K. McKay ◽  
James P. White
Keyword(s):  
Cell Cycle Progression ◽  
Kinase Inhibitor ◽  
Metabolic Stress ◽  
Subcellular Location ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Cyclin Dependent Kinase Inhibitor ◽  
Cytoskeletal Dynamics ◽  
Novel Target

Once believed to solely function as a cyclin-dependent kinase inhibitor, p27Kip1 is now emerging as a critical mediator of autophagy, cytoskeletal dynamics, cell migration and apoptosis. During periods of metabolic stress, the subcellular location of p27Kip1 largely dictates its function. Cytoplasmic p27Kip1 has been found to be promote cellular resilience through autophagy and anti-apoptotic mechanisms. Nuclear p27Kip1, however, inhibits cell cycle progression and makes the cell susceptible to quiescence, apoptosis, and/or senescence. Cellular location of p27Kip1 is regulated, in part, by phosphorylation by various kinases, including Akt and AMPK. Aging promotes nuclear localization of p27Kip1 and a predisposition to senescence or apoptosis. Here, we will review the role of p27Kip1 in healthy and aging cells with a particular emphasis on the interplay between autophagy and apoptosis.

scholarly journals A Functional Role of the Cyclin-Dependent Kinase Inhibitor 1 (P21WAF1/CIP1) for Neuronal Preconditioning

2013 ◽  
Vol 33 (3) ◽  
pp. 351-355 ◽  
Author(s):  
Philipp Mergenthaler ◽  
Claudia Muselmann ◽  
Juliane Sünwoldt ◽  
Nickolay K Isaev ◽  
Tadeusz Wieloch ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Target Gene ◽  
Kinase Inhibitor ◽  
Hypoxia Inducible Factor ◽  
Hypoxic Preconditioning ◽  
Posttranslational Regulation ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Cyclin Dependent Kinase Inhibitor

Hypoxic preconditioning is thought to rely on gene products regulated by hypoxia-inducible factor (HIF)-1. Here, we show that the HIF-1 target gene cyclin-dependent kinase inhibitor 1, p21 WAF1/CIP1, is essential for neuroprotection by hypoxic/aglycemic or erythropoietin preconditioning using wild-type and p21 WAF1/CIP1-deficient neurons. Furthermore, overexpression of wild-type p21 WAF1/CIP1 or phospho-mutants significantly increased cell death after hypoxia/aglycemia. Moreover, deferoxamine-induced endogenous tolerance did not involve p21 WAF1/CIP1 expression in cortical neurons. Our data suggest that balanced expression and potentially posttranslational regulation of p21 WAF1/CIP1 is required for hypoxic preconditioning.

scholarly journals Glucose Inhibits Meiotic DNA Replication through SCFGrr1p-Dependent Destruction of Ime2p Kinase

2005 ◽  
Vol 25 (1) ◽  
pp. 440-450 ◽  
Author(s):  
Kedar Purnapatre ◽  
Misa Gray ◽  
Sarah Piccirillo ◽  
Saul M. Honigberg
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Kinase Inhibitor ◽  
Cell Division Cycle ◽  
Mutant Form ◽  
Sporulation Medium ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Cell Fates ◽  
Cyclin Dependent Kinase Inhibitor

ABSTRACT In the budding yeast Saccharomyces cerevisiae, the cell division cycle and sporulation are mutually exclusive cell fates; glucose, which stimulates the cell division cycle, is a potent inhibitor of sporulation. Addition of moderate concentrations of glucose (0.5%) to sporulation medium did not inhibit transcription of two key activators of sporulation, IME1 and IME2, but did increase levels of Sic1p, a cyclin-dependent kinase inhibitor, resulting in a block to meiotic DNA replication. The effects of glucose on Sic1p levels and DNA replication required Grr1p, a component of the SCFGrr1p ubiquitin ligase. Sic1p is negatively regulated by Ime2p kinase, and several observations indicate that glucose inhibits meiotic DNA replication through SCFGrr1p-mediated destruction of this kinase. First, Ime2p was destabilized in the presence of glucose, and this turnover required Grr1p, a second component of SCFGrr1p, Cdc53p, and an SCFGrr1p-associated E2 enzyme, Cdc34p. Second, Ime2p-ubiquitin conjugates were detected under conditions of rapid Ime2p turnover, and conjugation of Ime2p to ubiquitin required GRR1. Third, a mutant form of Ime2p (Ime2ΔPEST), in which a putative Grr1p-interacting sequence was deleted, was more stable than wild-type Ime2p. Finally, expression of the IME2 ΔPEST allele bypassed the block to meiotic DNA replication caused by 0.5% glucose. In addition, Grr1p is required for later events in sporulation independently of its role in Ime2p turnover.

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