Gene expression modulation by the linker of nucleoskeleton and cytoskeleton complex contributes to proteostasis.

Amir Levine,Ehud Cohen,Danielle Grushko

doi:10.1111/acel.13047

Amir Levine, Ehud Cohen + Show 1 more

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https://doi.org/10.1111/acel.13047

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Journal: Aging Cell	Publication Date: Oct 1, 2019
Citations: 8	License type: CC BY 4.0

Affiliation: Hebrew University of Jerusalem

Abstract

Cellular mechanisms that act in concert to maintain protein homeostasis (proteostasis) are vital for organismal functionality and survival. Nevertheless, subsets of aggregation‐prone proteins form toxic aggregates (proteotoxicity) that in some cases, underlie the development of neurodegenerative diseases. Proteotoxic aggregates are often deposited in the vicinity of the nucleus, a process that is cytoskeleton‐dependent. Accordingly, cytoskeletal dysfunction contributes to pathological hallmarks of various neurodegenerative diseases. Here, we asked whether the linker of nucleoskeleton and cytoskeleton (LINC) complex, which bridges these filaments across the nuclear envelope, is needed for the maintenance of proteostasis. Employing model nematodes, we discovered that knocking down LINC components impairs the ability of the worm to cope with proteotoxicity. Knocking down anc‐1, which encodes a key component of the LINC complex, modulates the expression of transcription factors and E3 ubiquitin ligases, thereby affecting the rates of protein ubiquitination and impairing proteasome‐mediated protein degradation. Our results establish a link between the LINC complex, protein degradation, and neurodegeneration‐associated proteotoxicity.

Highlights

Maintaining cellular protein homeostasis requires a coordinated network of quality control and degradation mechanisms, and is vital for organismal functionality and survival (Balch et al, 2008)
Using RNA interference (RNAi), we knocked down the expression of each one of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex genes: sun-1, unc-84, zyg-12, or anc-1, and followed the rates of paralysis within the populations
Our results indicate that the knockdown of any of these genes enhances paralysis compared to feeding the worms with control bacteria that harbor the empty RNAi vector (EV) (Figure 1A-1D)

Summary

Introduction

Maintaining cellular protein homeostasis (proteostasis) requires a coordinated network of quality control and degradation mechanisms (the “proteostasis network”), and is vital for organismal functionality and survival (Balch et al, 2008). Late-onset neurodegenerative disorders, such as Alzheimer’s disease (AD) and Huntington’s disease (HD), are such maladies that are characterized by the accumulation of aberrantly aggregated proteins (Ross and Poirier, 2004). Cells form quality-control deposition sites that accumulate aberrantly aggregated proteins within the nucleoplasm (Miller et al, 2015). In some cases, aggregated proteins are deposited in juxta-nuclear quality control sites such as aggresomes of mammalian cells. Abnormal cytoskeletal components can accumulate in protein deposition sites, and underlie pathological aspects of neurodegenerative disorders (Collard et al, 1995; Goldman et al, 1983). The cytoskeleton is essential for protein deposition in quality-control sites and its stability is associated with increased proteostasis (Hill et al, 2017)

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