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      Aggregation of the nucleic acid–binding protein TDP-43 occurs via distinct routes that are coordinated with stress granule formation

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      Journal of Biological Chemistry
      American Society for Biochemistry & Molecular Biology (ASBMB)

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          Abstract

          TAR DNA-binding protein 43 (TDP-43) is a nucleic acid–binding protein, and its aggregation represents the defining pathology in amyotrophic lateral sclerosis (ALS) and related proteinopathies. Recent studies implicate cytoplasmic stress granules (SGs) as hubs that may facilitate TDP-43 aggregation. Here, using cellular fractionation, biochemical analyses, and histological assays, we show that TDP-43 targeted to the cytoplasm has multiple fates. Whereas a TDP-43 subpopulation is indeed recruited to SGs, mature aggregated TDP-43, produced with aggregate-prone TDP-43 variants or exposure to oxidative stress, generates distinct TDP-43 inclusions that are surprisingly devoid of SGs. Consistent with this observation, we found that SG components are predominantly excluded from TDP-43 pathology in motor neurons from individuals with ALS. We generated de novo SGs by expressing the fragile X protein (FMRP) and found that rather than directly engaging TDP-43 aggregates, SGs can sequester the proteostasis factor histone deacetylase 6 (HDAC6) and thereby impede TDP-43 clearance from cells. These findings indicate that SGs form distinct cytoplasmic structures that can indirectly enhance TDP-43 aggregation. Therapeutic approaches that inhibit SG formation may therefore be effective at suppressing TDP-43–mediated toxicity in patients with ALS and related TDP-43 proteinopathies.

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          Most cited references30

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          Stress granules: the Tao of RNA triage.

          Cytoplasmic RNA structures such as stress granules (SGs) and processing bodies (PBs) are functional byproducts of mRNA metabolism, sharing substrate mRNA, dynamic properties and many proteins, but also housing separate components and performing independent functions. Each can exist independently, but when coordinately induced they are often tethered together in a cytosolic dance. Although both self-assemble in response to stress-induced perturbations in translation, several recent reports reveal novel proteins and RNAs that are components of these structures but also perform other cellular functions. Proteins that mediate splicing, transcription, adhesion, signaling and development are all integrated with SG and PB assembly. Thus, these ephemeral bodies represent more than just the dynamic sorting of mRNA between translation and decay.
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            RNA granules: post-transcriptional and epigenetic modulators of gene expression.

            The composition of cytoplasmic messenger ribonucleoproteins (mRNPs) is determined by their nuclear and cytoplasmic histories and reflects past functions and future fates. The protein components of selected mRNP complexes promote their assembly into microscopically visible cytoplasmic RNA granules, including stress granules, processing bodies and germ cell (or polar) granules. We propose that RNA granules can be both a cause and a consequence of altered mRNA translation, decay or editing. In this capacity, RNA granules serve as key modulators of post-transcriptional and epigenetic gene expression.
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              HDAC6 controls autophagosome maturation essential for ubiquitin-selective quality-control autophagy.

              Autophagy is primarily considered a non-selective degradation process induced by starvation. Nutrient-independent basal autophagy, in contrast, imposes intracellular QC by selective disposal of aberrant protein aggregates and damaged organelles, a process critical for suppressing neurodegenerative diseases. The molecular mechanism that distinguishes these two fundamental autophagic responses, however, remains mysterious. Here, we identify the ubiquitin-binding deacetylase, histone deacetylase-6 (HDAC6), as a central component of basal autophagy that targets protein aggregates and damaged mitochondria. Surprisingly, HDAC6 is not required for autophagy activation; rather, it controls the fusion of autophagosomes to lysosomes. HDAC6 promotes autophagy by recruiting a cortactin-dependent, actin-remodelling machinery, which in turn assembles an F-actin network that stimulates autophagosome-lysosome fusion and substrate degradation. Indeed, HDAC6 deficiency leads to autophagosome maturation failure, protein aggregate build-up, and neurodegeneration. Remarkably, HDAC6 and F-actin assembly are completely dispensable for starvation-induced autophagy, uncovering the fundamental difference of these autophagic modes. Our study identifies HDAC6 and the actin cytoskeleton as critical components that define QC autophagy and uncovers a novel regulation of autophagy at the level of autophagosome-lysosome fusion.
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                Author and article information

                Journal
                Journal of Biological Chemistry
                J. Biol. Chem.
                American Society for Biochemistry & Molecular Biology (ASBMB)
                0021-9258
                1083-351X
                March 08 2019
                March 08 2019
                March 08 2019
                January 10 2019
                : 294
                : 10
                : 3696-3706
                Article
                10.1074/jbc.RA118.006351
                6416430
                30630951
                96f1cb09-f8a9-4649-889e-3422ba3d849a
                © 2019
                History

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