Regulation of the Myosin-Directed Chaperone UNC-45 by a Novel E3/E4-Multiubiquitylation Complex in C. elegans

Hoppe, Thorsten; Cassata, Giuseppe; Barral, José M.; Springer, Wolfdieter; Hutagalung, Alex H.; Epstein, Henry F.; Baumeister, Ralf

doi:10.1016/j.cell.2004.07.014

Cited by 136 publications

(149 citation statements)

References 35 publications

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“…ubq-1 and ubq-2 encode for C. elegans ubiquitin. RPT-2 is a regulatory proteasome particle and RNAi of rpt-2 has been shown to inhibit proteasome function in live C. elegans (26). As proteasome inactivation is lethal to developing worms, we initiated RNAi only in young adults.…”

Section: Host Ups Mediates Elt-2 Degradation During B Pseudomalleimentioning

confidence: 99%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

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

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Burkholderia pseudomallei is a Gram-negative soil bacterium that infects both humans and animals. Although cell culture studies have revealed significant insights into factors contributing to virulence and host defense, the interactions between this pathogen and its intact host remain to be elucidated. To gain insights into the host defense responses to B. pseudomallei infection within an intact host, we analyzed the genome-wide transcriptome of infected Caenorhabditis elegans and identified ∼6% of the nematode genes that were significantly altered over a 12-h course of infection. An unexpected feature of the transcriptional response to B. pseudomallei was a progressive increase in the proportion of down-regulated genes, of which ELT-2 transcriptional targets were significantly enriched. ELT-2 is an intestinal GATA transcription factor with a conserved role in immune responses. We demonstrate that B. pseudomallei down-regulation of ELT-2 targets is associated with degradation of ELT-2 protein by the host ubiquitin-proteasome system. Degradation of ELT-2 requires the B. pseudomallei type III secretion system. Together, our studies using an intact host provide evidence for pathogen-mediated host immune suppression through the destruction of a host transcription factor.innate immunity | ubiquitin-proteosomal system

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Section: Host Ups Mediates Elt-2 Degradation During B Pseudomalleimentioning

confidence: 99%

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Lee

Wong

Chin

et al. 2013

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

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“…However, both body wall and pharyngeal muscle also contain the invertebrate paramyosin core protein encoded by unc-15 (Epstein et al, 1985;Kagawa et al, 1989). The extensive similarities to mammalian muscle have allowed C. elegans to be developed as a small animal model for studies of a number of types of muscle atrophy, including muscular dystrophy (Grisoni et al, 2002), starvation (Zdinak et al, 1997), denervation (Szewczyk et al, 2000), growth factor alterations (Szewczyk and Jacobson, 2003), aging (Fisher, 2004) and altered function of myosin chaperones (Hoppe et al, 2004). C. elegans has also been developed as a model for studies of spaceflight effects on physiology (Hartman et al, 2001;Nelson et al, 1994a;Nelson et al, 1994b).…”

Section: Introductionmentioning

confidence: 99%

Decreased expression of myogenic transcription factors and myosin heavy chains inCaenorhabditis elegansmuscles developed during spaceflight

Higashibata

Szewczyk

Conley

et al. 2006

Journal of Experimental Biology

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SUMMARY The molecular mechanisms underlying muscle atrophy during spaceflight are not well understood. We have analyzed the effects of a 10-day spaceflight on Caenorhabditis elegans muscle development. DNA microarray, real-time quantitative PCR, and quantitative western blot analyses revealed that the amount of MHC in both body-wall and pharyngeal muscle decrease in response to spaceflight. Decreased transcription of the body-wall myogenic transcription factor HLH-1 (CeMyoD) and of the three pharyngeal myogenic transcription factors, PEB-1, CEH-22 and PHA-4 were also observed. Upon return to Earth animals displayed reduced rates of movement, indicating a functional defect. These results demonstrate that C. elegans muscle development is altered in response to spaceflight. This altered development occurs at the level of gene transcription and was observed in the presence of innervation,not simply in isolated cells. This important finding coupled with past observations of decreased levels of the same myogenic transcription factions in vertebrates after spaceflight raises the possibility that altered muscle development is a contributing factor to spaceflight-induced muscle atrophy in vertebrates.

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“…The protein was first described as a chaperone for myosin folding (12)(13)(14)(15)(16)(17)(18)(19). Subsequent reports invoked UCS in protecting myosin from degradation (20,21) and in enhancing the binding of the motor domain of myosin to actin filaments (21,22).…”

mentioning

confidence: 99%

UNC-45/CRO1/She4p (UCS) protein forms elongated dimer and joins two myosin heads near their actin binding region

Shi

Blobel

2010

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

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UNC-45/CRO1/She4p (UCS) proteins have variously been proposed to affect the folding, stability, and ATPase activity of myosins. They are the only proteins known to interact directly with the motor domain. To gain more insight into UCS function, we determined the atomic structure of the yeast UCS protein, She4p, at 2.9 Å resolution. We found that 16 helical repeats are organized into an L-shaped superhelix with an amphipathic N-terminal helix dangling off the short arm of the L-shaped molecule. In the crystal, She4p forms a 193-Å-long, zigzag-shaped dimer through three distinct and evolutionary conserved interfaces. We have identified She4p’s C-terminal region as a ligand for a 27-residue-long epitope on the myosin motor domain. Remarkably, this region consists of two adjacent, but distinct, binding epitopes localized at the nucleotide-responsive cleft between the nucleotide- and actin-filament-binding sites. One epitope is situated inside the cleft, the other outside the cleft. After ATP hydrolysis and Pi ejection, the cleft narrows at its base from 20 to 12 Å thereby occluding the inside the cleft epitope, while leaving the adjacent, outside the cleft binding epitope accessible to UCS binding. Hence, one cycle of higher and lower binding affinity would accompany one ATP hydrolysis cycle and a single step in the walk on an actin filament rope. We propose that a UCS dimer links two myosins at their motor domains and thereby functions as one of the determinants for step size of myosin on actin filaments.

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Regulation of the Myosin-Directed Chaperone UNC-45 by a Novel E3/E4-Multiubiquitylation Complex in C. elegans

Cited by 136 publications

References 35 publications

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Burkholderia pseudomallei suppresses Caenorhabditis elegans immunity by specific degradation of a GATA transcription factor

Decreased expression of myogenic transcription factors and myosin heavy chains inCaenorhabditis elegansmuscles developed during spaceflight

UNC-45/CRO1/She4p (UCS) protein forms elongated dimer and joins two myosin heads near their actin binding region

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