The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy

Janiesch, Philipp Christoph; Kim, Johnny; Mouysset, Julien; Barikbin, R; Lochmüller, Hanns; Cassata, Giuseppe; Krause, Sabine; Hoppe, Thorsten

doi:10.1038/ncb1554

Cited by 136 publications

(162 citation statements)

References 42 publications

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“…UNC-45b-deficient zebrafish embryos and worms have strongly disorganized sarcomeres, although initial Zbody formation and the basal organization of thick filaments seems not to be altered, implicating a rather restricted role of UNC-45b in the integration of thick filaments into sarcomeres (Barral et al, 2002;Etard et al, 2007). Strikingly, not only the loss but also elevated levels of UNC-45b result in inhibition of sarcomere assembly in worms and zebrafish, indicating that muscle chaperone levels have to be precisely balanced for unconstrained sarcomerogenesis and myosin stability (Bernick et al, 2010;Hoppe et al, 2004;Janiesch et al, 2007;Landsverk et al, 2007). We find UNC-45b expression levels to be severely upregulated in fla. Interestingly, a mild knockdown of UNC-45b in fla mutant embryos does not reconstitute heart and skeletal muscle function, implying that overexpression of UNC-45b is not the molecular cause of the observed muscle phenotype in fla.…”

Section: Discussionmentioning

confidence: 99%

The myosin-interacting protein SMYD1 is essential for sarcomere organization

et al. 2011

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SummaryAssembly, maintenance and renewal of sarcomeres require highly organized and balanced folding, transport, modification and degradation of sarcomeric proteins. However, the molecules that mediate these processes are largely unknown. Here, we isolated the zebrafish mutant flatline (fla), which shows disturbed sarcomere assembly exclusively in heart and fast-twitch skeletal muscle. By positional cloning we identified a nonsense mutation within the SET-and MYND-domain-containing protein 1 gene (smyd1) to be responsible for the fla phenotype. We found SMYD1 expression to be restricted to the heart and fast-twitch skeletal muscle cells. Within these cell types, SMYD1 localizes to both the sarcomeric M-line, where it physically associates with myosin, and the nucleus, where it supposedly represses transcription through its SET and MYND domains. However, although we found transcript levels of thick filament chaperones, such as Hsp90a1 and UNC-45b, to be severely upregulated in fla, its histone methyltransferase activity -mainly responsible for the nuclear function of SMYD1 -is dispensable for sarcomerogenesis. Accordingly, sarcomere assembly in fla mutant embryos can be reconstituted by ectopically expressing histone methyltransferase-deficient SMYD1. By contrast, ectopic expression of myosinbinding-deficient SMYD1 does not rescue fla mutants, implicating an essential role for the SMYD1-myosin interaction in cardiac and fast-twitch skeletal muscle thick filament assembly.

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Section: Discussionmentioning

confidence: 99%

The myosin-interacting protein SMYD1 is essential for sarcomere organization

et al. 2011

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“…Ufd3, in contrast, stabilizes substrates due to its antagonistic binding to Cdc48 [52]. In higher eukaryotes, Ufd2 controls myosin assembly and myofibril organization by catalyzing the degradation of the myosin-specific chaperone, UNC-45 [81,82]. While Ufd2 and Ufd3 provide an additional layer of control in certain Cdc48-dependent degradation pathways, other substrate-processing cofactors appear to execute their (enzymatic) function on predetermined substrates without further regulatory impact.…”

Section: Npl4mentioning

confidence: 99%

UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

Schuberth¹,

Buchberger

2008

Cell. Mol. Life Sci.

258

275

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Abstract. The highly conserved AAA ATPase Cdc48/ p97 acts on ubiquitylated substrate proteins in cellular processes as diverse as the fusion of homotypic membranes and the degradation of misfolded proteins. The Ubiquitin regulatory X (UBX) domaincontaining proteins constitute the so far largest family of Cdc48/p97 cofactors. UBX proteins are involved in substrate recruitment to Cdc48/p97 and in the temporal and spatial regulation of its activity. In combination with UBX-like proteins and other cofactors, they can assemble into a large variety of Cdc48/p97-cofactor complexes possessing distinct cellular functions. This review gives an overview of the different subfamilies of UBX proteins and their functions, and discusses general principles of Cdc48/p97 regulation by these cofactors.

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“…In recent studies, the ATPase p97/VCP of the AAA (ATPases associated with diverse cellular activities) family has been implicated in the proteasomal degradation of certain cytosolic substrates (9)(10)(11)(12)(13). VCP is capable of dissociating proteins from large cellular structures such as the endoplasmic reticulum (14), the mitotic spindle (12), the nuclear envelope (15), and chromatin (16).…”

Section: Intracellular Immunity | Cdc48mentioning

confidence: 99%

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

Hauler

Mallery

McEwan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Tripartite motif-containing 21 (TRIM21) is a cytosolic IgG receptor that mediates intracellular virus neutralization by antibody. TRIM21 targets virions for destruction in the proteasome, but it is unclear how a substrate as large as a viral capsid is degraded. Here, we identify the ATPase p97/valosin-containing protein (VCP), an enzyme with segregase and unfoldase activity, as a key player in this process. Depletion or catalytic inhibition of VCP prevents capsid degradation and reduces neutralization. VCP is required concurrently with the proteasome, as addition of inhibitor after proteasomal degradation has no effect. Moreover, our results suggest that it is the challenging nature of virus as a substrate that necessitates involvement of VCP, since intracellularly expressed IgG Fc is degraded in a VCP-independent manner. These results implicate VCP as an important host factor in antiviral immunity.A ntibody neutralization is a key component of the antiviral response and provides protective immunity. Our recent work has shown that neutralization can occur inside cells, in an effector-driven process mediated by tripartite motif-containing 21 (TRIM21). TRIM21, a cytosolic antibody receptor of ultrahigh affinity to IgG Fc (1, 2), is recruited to antibody-bound virus and targets the complex to the proteasome for degradation (3). This process potently neutralizes viral infection and has been termed antibody-dependent intracellular neutralization (ADIN) (4). ADIN is dependent upon the E3 ubiquitin ligase activity of TRIM21 and can be abrogated by chemical inhibition of the proteasome.Although both proteasomal activity and ubiquitination are necessary for ADIN, the exact mechanism of virus degradation is poorly understood. Specifically, it is not clear how the proteasome can degrade a virion, a compact proteinaceous particle much larger than the proteasome itself. The 26S proteasome has a mass of ∼2.5 MDa (5), and the pore through which substrates must pass to access the proteolytic chamber is no greater than 2 nm in diameter (6, 7). In contrast, human adenovirus (AdV), a virus potently neutralized by TRIM21, has a diameter of ∼100 nm and a mass of 150 MDa (8).Although there are ATPases in the 19S regulatory subunit of the 26S proteasome that may unfold substrates and allow them to enter through the pore (5, 6), AdV virions are much larger than any of the proteasome's known cellular substrates. Because ADIN has been shown to be independent of autophagy but dependent on proteasomal degradation (3), we hypothesized that an additional energydependent step of AdV capsid disassembly and/or unfolding might precede proteasomal degradation of the virus.In recent studies, the ATPase p97/VCP of the AAA (ATPases associated with diverse cellular activities) family has been implicated in the proteasomal degradation of certain cytosolic substrates (9-13). VCP is capable of dissociating proteins from large cellular structures such as the endoplasmic reticulum (14), the mitotic spindle (12), the nuclear envelope (15), and chromatin (1...

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The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy

Cited by 136 publications

References 42 publications

The myosin-interacting protein SMYD1 is essential for sarcomere organization

The myosin-interacting protein SMYD1 is essential for sarcomere organization

UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization

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