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The metacaspase Yca1 maintains proteostasis through multiple interactions with the ubiquitin system.

ABSTRACT: Metacaspase enzymes are critical regulatory factors that paradoxically engage apoptosis and also maintain cell viability. For example, the Saccharomyces cerevisiae metacaspase Yca1 has been shown to be important for maintaining cellular proteostasis during stress, and the loss of this enzyme results in increased retention of aggregated material within the insoluble proteome. However, the molecular mechanism(s) by which Yca1 maintains cellular proteostasis remains unknown. Here, using proteomic analysis coupled with protein interaction studies we identified a direct interplay between Yca1 and the ubiquitin-proteasome system. We noted multiple ubiquitination sites on Yca1 and established Rsp5 as the candidate E3 ligase involved in this process. Further characterization of the ubiquitination sites identified the K355 residue on Yca1 as a critical modification for proteostasis function, managing both insoluble protein content and vacuolar response. We also identified a Yca1 phosphorylation site at S346, which promoted interaction with Rsp5 and the aggregate dispersal function of the metacaspase. Interestingly, proteomic analysis also revealed that Yca1 interacts with the ubiquitin precursor protein Rps31, cleaving the protein to release free ubiquitin. In turn, loss of Yca1 or its catalytic activity reduced the levels of monomeric ubiquitin in vivo, concurrent to increased protein aggregation. The K355 and S346 residues were also observed to influence the abundance of low-molecular weight ubiquitin. Together, these observations suggest that Yca1 maintains proteostasis and limits protein aggregation by ensuring a free flow of monoubiquitin, an essential precursor for ligase-enhanced Yca1 enzymatic activity and general proteasome-mediated protein degradation.

SUBMITTER: Shrestha A

PROVIDER: S-EPMC6341073 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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The metacaspase Yca1 maintains proteostasis through multiple interactions with the ubiquitin system.

Shrestha Amit A Brunette Steve S Stanford William Lloyd WL Megeney Lynn Arthur LA

Cell discovery 20190122

Metacaspase enzymes are critical regulatory factors that paradoxically engage apoptosis and also maintain cell viability. For example, the <i>Saccharomyces cerevisiae</i> metacaspase Yca1 has been shown to be important for maintaining cellular proteostasis during stress, and the loss of this enzyme results in increased retention of aggregated material within the insoluble proteome. However, the molecular mechanism(s) by which Yca1 maintains cellular proteostasis remains unknown. Here, using prot ...[more]

PMID: 30675380

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Project description:Appropriate excitatory/inhibitory (E/I) balance is essential for normal cortical function and is altered in some psychiatric disorders, including autism spectrum disorders (ASDs). Cell-autonomous molecular mechanisms that control the balance of excitatory and inhibitory synapse function remain poorly understood; no proteins that regulate excitatory and inhibitory synapse strength in a coordinated reciprocal manner have been identified. Using super-resolution imaging, electrophysiology, and molecular manipulations, we show that cadherin-10, encoded by CDH10 within the ASD risk locus 5p14.1, maintains both excitatory and inhibitory synaptic scaffold structure in cultured cortical neurons from rats of both sexes. Cadherin-10 localizes to both excitatory and inhibitory synapses in neocortex, where it is organized into nanoscale puncta that influence the size of their associated PSDs. Knockdown of cadherin-10 reduces excitatory but increases inhibitory synapse size and strength, altering the E/I ratio in cortical neurons. Furthermore, cadherin-10 exhibits differential participation in complexes with PSD-95 and gephyrin, which may underlie its role in maintaining the E/I ratio. Our data provide a new mechanism whereby a protein encoded by a common ASD risk factor controls E/I ratios by regulating excitatory and inhibitory synapses in opposing directions.SIGNIFICANCE STATEMENT The correct balance between excitatory/inhibitory (E/I) is crucial for normal brain function and is altered in psychiatric disorders such as autism. However, the molecular mechanisms that underlie this balance remain elusive. To address this, we studied cadherin-10, an adhesion protein that is genetically linked to autism and understudied at the cellular level. Using a combination of advanced microscopy techniques and electrophysiology, we show that cadherin-10 forms nanoscale puncta at excitatory and inhibitory synapses, maintains excitatory and inhibitory synaptic structure, and is essential for maintaining the correct balance between excitation and inhibition in neuronal dendrites. These findings reveal a new mechanism by which E/I balance is controlled in neurons and may bear relevance to synaptic dysfunction in autism.

Dataset Information

The metacaspase Yca1 maintains proteostasis through multiple interactions with the ubiquitin system.

Publications

The metacaspase Yca1 maintains proteostasis through multiple interactions with the ubiquitin system.

Similar Datasets

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