| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | ADVANCED SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Molecular Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan
 |
Abstract |
|---|
 Top Abstract IntroductionResultsDiscussionExperimental proceduresReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
p97 is one of the best characterized members of the AAA (ATPases associated with diverse cellular activities) family and forms a complex with Npl4 and Ufd1 subunits, which are essential for ERAD function of p97 (Ye et al. 2001; Mouysset et al. 2006; Ye 2006). In concert with ubiquitination by ER-membrane resident E3 ubiquitin ligases, p97 extracts ERAD substrates from the ER to the cytosol using energy produced by p97-catalyzed ATP hydrolysis. Several reports have demonstrated that E3 ubiquitin ligases (Hrd1, gp78 and Doa10p) directly associate with p97 (Zhong et al. 2004; Ye et al. 2005; Carvalho et al. 2006). Extracted and ubiquitinated substrates will be transferred to the 26S proteasome through Ufd2 and Rad23. Rpn10 and Rpt5 subunits of the proteasome are receptors for ubiquitinated substrates. Thus, the interaction between p97 and E3 ubiquitin ligases may lead to efficiently couple ubiquitination with retrotranslocation and degradation of ERAD substrates.
Ubiquitination of ERAD substrates appears to take place at the cytosolic face of the ER membrane during or prior to retrotranslocation to the cytosol (Hampton 2002; Ye et al. 2005). In the yeast Saccharomyces cerevisiae, there are two ER-membrane resident E3 ubiquitin ligases Hrd1p/Der3p and Doa10p/Ssm4p (Bays et al. 2001; Deak & Wolf 2001; Swanson et al. 2001; Hampton 2002; Römisch 2005; Gauss et al. 2006; Ravid et al. 2006). It has been recently proposed that two distinct protein complexes containing a specific E3 ubiquitin ligase at the ER membrane are responsible for the recognition and degradation of specific subsets of protein substrates (Huyer et al. 2004; Vashist & Ng 2004; Carvalho et al. 2006; Denic et al. 2006). A complex containing Hrd1p catalyzes ubiquitination of ERAD substrates with lesions, which are surveyed by ER chaperone BiP, in the lumen or membrane-spanning region. On the other hand, the other complex containing Doa10p ubiquitinates transmembrane ERAD substrates with lesions in the cytosolic domain, which are surveyed by the cytosolic Hsp70 chaperone Ssa1p and the Hsp40 co-chaperones Ydj1p and Hlj1p.
Although many ERAD components have been identified and their biochemical properties have been revealed, their cellular functions have not been well understood. Here, we investigated their cellular functions in Caenorhabditis elegans as a model organism. By monitoring the expression of an ER chaperone gene and analyzing phenotypes of mutant worms of p97 and E3 ubiquitin ligases, we found that p97 and the E3 ubiquitin ligase HRD-1 play essential roles in unfolded protein response (UPR) and ERAD pathways. We further found that HRD-1 functions in concert with the ER resident chaperone BiP in growth and organ development, and that two BiP homologues of C. elegans are functionally diversified.
|
Results |
|---|
|
TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
Caenorhabditis elegans possesses two genes, cdc-48.1 and cdc-48.2, encoding p97 of 88% identity over the entire protein and both homologues are essential for embryogenesis in a redundant manner (Yamanaka et al. 2004). To analyze effects of simultaneous disruption of two p97 homologues on post-embryonic development, we took advantage of feeding RNAi strategy (Kamath et al. 2001). L1 larvae were fed with E. coli harboring dsRNA-producing plasmids, and worms were analyzed 2 days later. Vector plasmid-harboring E. coli was used for feed as a control experiment. As shown in Fig. 1A, dark staining large intestinal granules were observed in p97-depleted worms, while such granules were not observed in control worms. Note that single deletion mutant, either cdc-48.1(tm544) or cdc-48.2(tm659), did not cause such granules (data not shown). Intestinal cells engage in high level secretory protein synthesis, such as digestive enzymes and molting hormones, and are major targets for ER stress in C. elegans (Shen et al. 2001; Calfon et al. 2002), implying that impairment of ERAD by p97 depletion may cause accumulation of secretory proteins in the ER of intestinal cells. It should be mentioned that worms with a blocked UPR have been observed to have such dark staining large intestinal granules (Urano et al. 2002). These results indicate the importance of p97 in UPR and ERAD pathways.
|
Homologues of Hrd1, gp78 and MARCH VI/Doa10p in Caenorhabditis elegans
It has been demonstrated that ER-membrane resident E3 ubiquitin ligases are key components involved in the recognition and ubiquitination of substrates, which may be coupled with the retrotranslocation mediated by p97, in the ERAD pathways (Hampton 2002; Römisch 2005). While yeast possesses two E3 ubiquitin ligases Hrd1p and Doa10p, there are three ligases in mammals, two homologues of Hrd1p, Hrd1 and gp78/AMFR, and a Doa10p homologue TEB4/MARCH VI (Bays et al. 2001; Deak & Wolf 2001; Swanson et al. 2001; Hampton 2002; Zhong et al. 2004; Römisch 2005; Gauss et al. 2006; Kreft et al. 2006; Ravid et al. 2006). There are 152 RING finger proteins in the C. elegans genome (Kipreos 2005). Among them, we found that 16 proteins contain putative transmembrane domains by using the topological prediction program TMHMM version 2.0 <http://www.cbs.dtu.dk/services/TMHMM/> (Krogh et al. 2001). Homology search analysis of these 16 proteins with the amino acid sequences of ER E3 ubiquitin ligases revealed that C. elegans possesses each homologue of Hrd1, gp78 and MARCH VI [named as HRD-1 (F55A11.3), HRDL-1 (F26E4.11) and MARC-6 (F55A3.1), respectively] (Fig. 2A). As shown in Fig. 2B, in addition to the RING finger domain, they also contain multiple membrane-spanning regions (6, 8 and 12 predicted transmembrane domains for HRD-1, HRDL-1 and MARC-6, respectively). The RING finger domain of HRD-1 and HRDL-1 is situated in the C terminal region, while that of MARC-6 exists in the N terminal domain. Furthermore, HRDL-1 contains a CUE motif, which serves as an ubiquitin-binding domain (Zhong et al. 2004). All these characteristic features are well conserved evolutionarily.
|
hrd-1(tm1743) deletion mutant showed a slightly slow growth rate, whereas hrdl-1(gk28) deletion and RNAi depletion of marc-6 did not affect the growth rate (Fig. 3A). We confirmed that marc-6 mRNA was significantly decreased by marc-6 RNAi treatment (Supplementary Fig. S2). Although hrdl-1(gk28) or marc-6(RNAi) was introduced into the hrd-1(tm1743) deletion mutant, the growth rate was not affected (Fig. 3A). However, when all three E3 ubiquitin ligases were simultaneously depleted, the growth rate was greatly reduced (Fig. 3A,B), suggesting that HRD-1, HRDL-1 and MARC-6 play an important redundant role on growth under the physiological condition.
|
Involvement of E3 ubiquitin ligases in UPR
We next tried to elucidate whether ERAD components of C. elegans are involved in UPR by using the hsp-4::gfp expression monitoring system as described above. The p97 adaptor UFD-1 was clearly involved in UPR in an ire-1-dependent manner (Fig. 4A). This is fully consistent with the results recently reported independently (Mouysset et al. 2006). Depletion of other p97 adaptors or associated factors (UFD-3, ATX-3 and Erasin homologue UBXN-4) did not induce the hsp-4::gfp expression (Fig. 4A; data for ATX-3 and UBXN-4 not shown). These results together strongly indicate that p97-Npl-4-Ufd-1 complex is involved in UPR in an ire-1/xbp-1-dependent manner.
|
ufd-2(tm1380), rpn-10(tm1180) and rpt-5(RNAi) did not induce the hsp-4::gfp expression (Fig. 4A). These results together indicate that ERAD components located upstream of the p97-Npl4-Ufd1 complex in the ERAD pathway are in general involved in UPR, while its downstream components are not. Since downstream components are located in the cytosol and are not specific for ERAD but common for ubiquitin-dependent degradation substrates, it is reasonable to assume that their depletion does not induce the ER chaperone BiP.
Genetic interaction between HRD-1 and BiP
We then examined the relationship between E3 ubiquitin ligases and ER chaperone BiP. In C. elegans, two genes, hsp-3 and hsp-4, encode highly homologous BiP proteins (85% identical, 92% similar). Their expression is regulated in a similar manner (Shen et al. 2001), but their functional diversity is not yet known. We found that hsp-3(ok1083);hsp-4(gk514) double deletion resulted in embryonic lethal, while no detectable defect in growth rate, morphology, fertility and embryogenesis was observed in each of single deletion (Fig. 5A, data not shown), indicating that they are essential and that their function is redundant. We prepared double mutants in combination of E3 ubiquitin ligases with BiP. Only in the case of combination of the HRD-1 deletion and the BiP deletion, clear defects were observed. As expected from results shown in Fig. 4A, expression of endogenous hsp-3 and hsp-4 genes was increased by the HRD-1 deletion (Supplementary Fig. S3). hrd-1(tm1743);hsp-3(ok1083) double mutant showed the extremely slow growth rate (6 days to become adult compared to 3 days for others) and the small body size phenotype (Fig. 5A). Furthermore, it had dark staining large intestinal granules (20 out of 20 analyzed) (Fig. 5B), which is a similar phenotype observed in p97-depleted, UFD-1-depleted or UPR-blocked worms (Figs 1A,D and 5B; Urano et al. 2002). In contrast, hrd-1(tm1743);hsp-4(gk514) mutant did not show these phenotypes (Fig. 5A,B). However, it showed the sterile phenotype (20 out of 20 analyzed), which is also observed in the p97-depleted and UFD-1-depleted worms, caused by the defect of gonad formation (Fig. 5C). It should be noted that expression of hrd-1, hrdl-1 and marc-6 was not affected by the depletion of BiP (Supplementary Fig. S3). These results imply that two kinds of BiP proteins encoded by hsp-3 and hsp-4 are functionally diversified. These results also indicate that HRD-1 and BiP have a genetic interaction, and that HRD-1 and BiP(HSP-3) play important roles in the developmental growth and function of intestinal cells, while HRD-1 and BiP(HSP-4) in the gonad formation.
|
|
Discussion |
|---|
|
TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
It is interesting to mention that proteasomes by themselves were reported to be responsible for retrotranslocation from the ER to the cytosol by means of direct association with the retrograde transport channel (Lee et al. 2004; Kalies et al. 2005; Römisch 2005). However, in our C. elegans system, depletion of RPN-10 and RPT-5, components of the proteasome and receptors for ubiquitinated substrates, did not induce the hsp-4::gfp expression (Fig. 4A), suggesting that proteasomes may not be directly involved in retrotranslocation of mis-folded proteins in C. elegans. Alternatively, there might be another pathway for retrotranslocation even though the proteasome-dependent pathway is blocked.
During or prior to retrotranslocation, ERAD substrates should be ubiquitinated at the cytosolic surface by ER-membrane resident E3 ubiquitin ligases (Hampton 2002; Römisch 2005). In mammals, three such ligases, Hrd-1, gp78/AMFR and TEB4/MARCH-VI, have been identified (Swanson et al. 2001; Hampton 2002; Zhong et al. 2004; Römisch 2005; Kreft et al. 2006). Caenorhabditis elegans was found to possess homologues for them (Fig. 2). We found that HRD-1 but not HRDL-1 and MARC-6 has a genetic interaction with BiP (Fig. 5). This is consistent with recent reports that two distinct protein complexes containing a specific E3 ubiquitin ligase at the ER membrane are responsible for the recognition and degradation of specific subsets of protein substrates (Huyer et al. 2004; Vashist & Ng 2004; Carvalho et al. 2006; Denic et al. 2006). It has been reported that Doa10p functionally interacts with cytosolic chaperone Ssa1p (Huyer et al. 2004). Since MARC-6 is a Doa10p homologue (Fig. 2), it seems likely that MARC-6 may function with an Ssa1 homologue. There is less information on gp78 so far. It is important to elucidate with which chaperone HRDL-1 (C. elegans gp78 homologue) functions. Nevertheless, we would like to propose that each E3 ubiquitin ligase functions in concert with a specific partner chaperone.
There are two BiP homologues, encoded by hsp-3 and hsp-4, in C. elegans and they are essential and functionally redundant (Shen et al. 2001; Calfon et al. 2002). However, their in vivo functions are somewhat diversified, as we observed that HRD-1 and BiP(HSP-3) play important roles in the developmental growth and function of intestinal cells, while HRD-1 and BiP(HSP-4) in the gonad formation. This selectivity may be due to the specifically overlapped tissue distribution of these proteins. Determination of their tissue distribution is important and remains elusive. In the same line, C. elegans uniquely possesses two p97 homologues as described previously (Yamanaka et al. 2004). Therefore, it is interesting to see if there is any specificity between two p97 homologues and three E3 ubiquitin ligases.
Since specific mutant proteins that accumulate as mis-folded proteins and escape degradation may cause various neurodegenerative diseases including Alzheimer's and Parkinson's diseases, it is likely that ER stress plays an important pathogenetic role in these diseases (Lindholm et al. 2006; Zhao & Ackerman 2006). It is interesting to mention that inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia has been demonstrated to be caused by mutations in p97 (Watts et al. 2004). We have reported that over-expression of p97 was able to significantly suppress the aggregation of expanded polyglutamine tracts (Yamanaka et al. 2004). In addition, it has been recently reported that over-expression of Hrd1 enhanced the degradation of expanded polyglutamine-containing huntingtin in a p97-dependent manner, whereas silencing of endogenous Hrd1 expression by RNA interference stabilized it (Yang et al. 2007). Thus, elucidation of UPR mechanisms and genetic interaction among factors involved in UPR in the model organism will allow us to understand not only the overall regulatory mechanism of the protein quality control system but also human diseases linked to ER stress such as inclusion body myopathy and various neurodegenerative disorders.
|
Experimental procedures |
|---|
|
TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
Nematodes were maintained at 20 °C on nutrient growth medium (NGM) agar plates using standard protocols as described previously (Brenner 1974). The deletion mutants of cdc-48.1(tm544), cdc-48.2(tm659), hrd-1(tm1743), ufd-2(tm1380) and rpn-10(tm1180) were kindly supplied from Dr S. Mitani (Tokyo Women's Medical School, Tokyo). Mutant worms SJ4005 hsp-4::gfp(zcls4), SJ30 ire-1(zc14);hsp-4::gfp(zcls4), SJ17 xbp-1(zc12);hsp-4::gfp(zcls4), VC35 hrdl-1(gk28), RB1104 hsp-3(ok1083) and VC1099 hsp-4(gk514) were provided by Caenorhabditis Genetics Center. To exclude unexpected additional mutations, deletion mutants were out-crossed 5 times. The hrdl-1(gk28), hsp-3(ok1083) and hsp-4(gk514) deletion alleles were sequenced and their mutation sites were registered to WormBase <http://www.wormbase.org>. The position and extent of each deletion mutation used in this study are schematically shown in Fig. 6. Males carrying mutations were generated from hermaphrodites of these deletion mutants and were used to transfer the mutation. The deletion alleles were confirmed by PCR with primers spanning the deletion region. hsp-3(ok1083);hsp-4(gk514) and hrd-1(tm1743);hsp-4(gk514) double deletion mutants were maintained as heterozygote. We used segregated double homozygotes.
|
Gravid hermaphrodites were placed on NGM agar plates containing 5 mM DTT or 5 µM thapsigargin for 2 h to lay eggs and then taken out. Plates harboring eggs were incubated at 20 °C for 3 days and growth stage of progeny was determined.
Plasmid construction
To prepare dsRNA-producing plasmids, portions of cDNA of cdc-48.1 (nucleotides 1–440) and cdc-48.2 (nucleotides 73–398) were excised from pCKX39 and pCKX36, respectively (Yamanaka et al. 2004), and cloned into a pLITMUS28 plasmid. Portions of cDNAs for ufd-1 (nucleotides 6–1017), ufd-3 (nucleotides 106–840), hrd-1 (nucleotides 92–776), hrdl-1 (nucleotides 65–955), marc-6 (nucleotides 186–1328) and rpt-5 (nucleotides 1–661) genes were prepared by RT-PCR using total RNA from N2 adult hermaphrodites or yk-plasmids as template with a pair of primers, 5'-CTT CAC TGC AGC GTG GAT ACA ACA AGG ACT TCA CGG GAT G-3' and 5'-CAG TCA GAT CTC AGT GTT CGA TTG CCT CCA CGG AAG AC-3', 5'-GGC TTC TGC AGT TAC TCA AGG CGG ATG CTT GAT ATC-3' and 5'-CAT GTA GAT CTT TGC CTC CAT CTA TTG CCC AAA ATT CAA-3', 5'-CAG TTG GAT CCA TCA ATC GTA TAT CTC TCA AAA AGC AAT GCA AGT ATG-3' and 5'-GAG GAA AGC TTT GTG AAG AGC TCT TAC TGA TTG ATA GAA CGG AC-3', 5'-GAG TGA GAT CTC TAT TAT CCG TGC TTA TGT ACA GGA AG-3' and 5'-TTA GGC TGC AGT TTC CAA TGC GAA ATG GGA AGT AC-3', and 5'-AGC GAA TTC ATG TCG CAA ACA CCA CCG CCA AAA GAC-3' and 5'-CAT GGA TCC TGG TGG TCC ATA CAT GAG CAC AC-3', respectively. Each DNA fragment was cloned into the pLITMUS28 vector.
Feeding RNAi
We employed Optimal Protocol I for feeding RNAi methods as described previously (Kamath et al. 2001). Briefly, dsRNA was produced in E. coli HT115(DE3) strain transformed with the dsRNA-producing plasmid. Isopropyl thio-ß-D-galactoside (1 mM) was added to NGM plates to induce transcription of the dsRNA. L1-staged hermaphrodites carrying an hsp-4::gfp reporter were placed on each RNAi plates for 72 h and observed under an Olympus SZX16 fluorescent microscope.
Microscopic observation
Whole worms were mounted on 1% agarose pads in 1 mg/mL levamisole diluted in M9 buffer. When necessary, chromosome DNA was stained with DAPI. Intestines were dissected in a slide chamber filled with M9 buffer. These samples were observed under an Olympus BX51 microscope equipped with a CCD camera. Adobe Photoshop 6.0 was used for output of images.
Western blotting analysis
Total lysates of worms were resolved on 10% SDS-PAGE and transferred to a nitrocellulose membrane. Signals were detected with the antibody against GFP or actin and quantified using a LAS1000 imager (Fuji Film). The amount of actin was used as loading control.
Phylogenetic analysis
Protein sequences were aligned using CLUSTALW. The phylogeny was constructed with the Neighbour-joining method using PHYLIP and was visualized using TREEVIEW software (Page 1996). Proteins analyzed: C. elegans HRD-1 (F55A11.3) (WP:CE05945), HRDL-1 (F26E4.11) (WP:CE09695), MARC-6 (F55A3.1) (WP:CE37022), H10E21.5 (WP:CE19490), C56A3.4 (WP:CE37961), Y4C6A.3 (WP:CE21299), M110.3 (WP:CE02276), C17E4.3 (WP:CE37199), Y53G8AM.4 (WP:CE25416), ZC13.1 (WP:CE29613), C17H11.6 (WP:CE27704), Y119C1B.5 (WP:CE27234), F58E6.1 (WP:CE25921), C16C10.5 (WP:CE01496), Y47D3B.11 (WP:CE33946) and Y57A10B.1 (WP:CE35688); Homo sapiens Hrd1 (BAC24801 [GenBank] ), gp78 (NP001135) and MARCH VI (NP005876); and S. cerevisiae Hrd1p (CAA99012 [GenBank] ) and Doa10p (P40318 [GenBank] ).
|
Acknowledgements |
|---|
|
Footnotes |
|---|
* Correspondence: E-mail: yamanaka{at}gpo.kumamoto-u.ac.jp
|
References |
|---|
|
TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
Brenner, S. (1974) The genetics of Caenorhabditis elegans. Genetics 77, 71–94.
Calfon, M., Zeng, H., Urano, F., Till, J.H., Hubbard, S.R., Harding, H.P., Clark, S.G. & Ron, D. (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96.[CrossRef][Medline]
Carvalho, P., Goder, V. & Rapoport, T.A. (2006) Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell 126, 361–373.[CrossRef][Medline]
Deak, P.M. & Wolf, D.H. (2001) Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J. Biol. Chem. 276, 10663–10669.
Denic, V., Quan, E.M. & Weissman, J.S. (2006) A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell 126, 349–359.[CrossRef][Medline]
Gauss, R., Sommer, T. & Jarosch, E. (2006) The Hrd1p ligase complex forms a linchpin between ER-luminal substrate selection and Cdc48p recruitment. EMBO J. 25, 1827–1835.[CrossRef][Medline]
Hampton, R.Y. (2002) ER-associated degradation in protein quality control and cellular regulation. Curr. Opin. Cell Biol. 14, 476–482.[CrossRef][Medline]
Huyer, G., Piluek, W.F., Fansler, Z., Kreft, S.G., Hochstrasser, M., Brodsky, J. & Michaelis, S. (2004) Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein. J. Biol. Chem. 279, 38369–39378.
Kalies, K.U., Allan, S., Sergeyenko, T., Kroger, H. & Römisch, K. (2005) The protein translocation channel binds proteasomes to the endoplasmic reticulum membrane. EMBO J. 24, 2284–2293.[CrossRef][Medline]
Kamath, R.S., Martinez-Campos, M., Zipperlen, P., Fraser, A.G. & Ahringer, J. (2001) Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, RESERCH0002.
Kipreos, E.T. (2005) Ubiquitin-mediated pathways in C. elegans. In: WormBook (ed. The C. elegans Research Community), WormBook, doi/10.1895/wormbook.1.36.1, <http://www.wormbook.org>.
Kreft, S.G., Wang, L. & Hochstrasser, M. (2006) Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). J. Biol. Chem. 281, 4646–4653.
Krogh, A., Larsson, B., von Heijne, G. & Sonnhammer, E.L. (2001) Predicting transmembrane topology with a hidden Markov model: application to complete genomes. J. Mol. Biol. 305, 567–580.[CrossRef][Medline]
Lee, R.J., Liu, C., Harty, C., McCracken, A.A., Römisch, K., DeMartino, G.N., Thomas, P.J. & Brodsky, J.L. (2004) The 19S cap of the 26S proteasome is sufficient to retro-translocate and deliver a soluble polypeptide for ER-associated degradation. EMBO J. 23, 2206–2215.[CrossRef][Medline]
Lilley, B. & Ploegh, H.L. (2004) A membrane protein required for dislocation of misfolded proteins from the ER. Nature 429, 834–840.[CrossRef][Medline]
Lilley, B. & Ploegh, H.L. (2005) Multiprotein complexes that link dislocation, ubiquitination, and extraction of misfolded proteins from the endoplasmic reticulum membrane. Proc. Natl. Acad. Sci. USA 102, 14296–14301.
Lindholm, D., Wootz, H. & Korhonen, L. (2006) ER stress and neurodegenerative diseases. Cell Death Differ. 13, 385–392.[CrossRef][Medline]
Ma, Y. & Hendershot, L.M. (2001) The unfolding tale of the unfolded protein response. Cell 107, 827–830.[CrossRef][Medline]
Mouysset, J., Kähler, C. & Hoppe, T. (2006) A conserved role of Caenorhabditis elegans CDC-48 in ER-associated protein degradation. J. Struct. Biol. 156, 41–49.[Medline]
Neuber, O., Jarosch, E., Volkwein, C., Walter, J. & Sommer, T. (2005) Ubx2 links the Cdc48 complex to ER-associated protein degradation. Nat. Cell Biol. 7, 993–998.[CrossRef][Medline]
Oda, Y., Okada, K., Yoshida, H., Kaufman, R.J., Nagata, K. & Mori, K. (2006) Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. J. Cell Biol. 172, 383–393.
Page, R.D. (1996) TREEVIEW: an application to display phylogenetic trees on personal computers. Comput. Appl. Biosci. 12, 357–358.
Ravid, T., Kreft, S.G. & Hochstrasser, M. (2006) Membrane and soluble substrates of the Doa10 ubiquitin ligase are degraded by distinct pathways. EMBO J. 25, 533–543.[CrossRef][Medline]
Römisch, K. (2005) Endoplasmic reticulum-associated degradation. Annu. Rev. Cell. Dev. Biol. 21, 435–456.[CrossRef][Medline]
Schuberth, C. & Buchberger, A. (2005) Membrane-bound Ubx2 recruits Cdc48 to ubiquitin ligases and their substrates to ensure efficient ER-associated protein degradation. Nat. Cell Biol. 7, 999–1006.[CrossRef][Medline]
Shen, X., Ellis, R.E., Lee, K., Liu, C.Y., Yang, K., Solomon, A., Yoshida, H., Morimoto, R., Kurnit, D.M., Mori, K. & Kaufman, R.J. (2001) Complementary signaling pathways regulate the unfolding protein response and are required for C. elegans development. Cell 107, 893–903.[CrossRef][Medline]
Swanson, R., Locher, M. & Hochstrasser, M. (2001) A conserved ubiquitin ligase of the nuclear envelope/endoplasmic reticulum that functions in both ER-associated and Matalpha2 repressor degradation. Genes. Dev. 15, 2660–2674.
Urano, F., Calfon, M., Yoneda, T., Yun, C., Kiraly, M., Clark, S.G. & Ron, D. (2002) A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response. J. Cell Biol. 158, 639–646.
Vashist, S. & Ng, D.T.W. (2004) Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control. J. Cell Biol. 165, 41–52.
Watts, G.D., Wymer, J., Kovach, M.J., Mehta, S.G., Mumm, S., Darvish, D., Pestronk, A., Whyte, M.P. & Kimonis, V.E. (2004) Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet. 36, 377–381.[CrossRef][Medline]
Yamanaka, K., Okubo, Y., Suzaki, T. & Ogura, T. (2004) Analysis of the two p97/VCP/Cdc48p proteins of Caenorhabditis elegans and their suppression of polyglutamine-induced protein aggregation. J. Struct. Biol. 146, 242–250.[CrossRef][Medline]
Yamauchi, S., Yamanaka, K. & Ogura, T. (2006) Comparative analysis of expression of two p97 homologues in Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 345, 746–753.[CrossRef][Medline]
Yang, H., Zhong, X., Ballar, P., Luo, S., Shen, Y., Rubinsztein, D.C., Monteiro, M.J. & Fang, S. (2007) Ubiquitin ligase Hrd1 enhances the degradation and suppresses the toxicity of polyglutamine-expanded huntingtin. Exp. Cell Res. 313, 538–550.[CrossRef][Medline]
Ye, Y. (2006) Diverse function with a common regulator: ubiquitin takes command of an AAA ATPase. J. Struct. Biol. 156, 29–40.[Medline]
Ye, Y., Meyer, H.H. & Rapoport, T.A. (2001) The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol. Nature 414, 652–656.[CrossRef][Medline]
Ye, Y., Shibata, Y., Kikkert, M., van Voorden, S., Wiertz, E. & Rapoport, T.A. (2005) Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane. Proc. Natl. Acad. Sci. USA 102, 14132–14138.
Ye, Y., Shibata, Y., Yun, C., Ron, D. & Rapoport, T.A. (2004) A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. Nature 429, 841–847.[CrossRef][Medline]
Zhao, L. & Ackerman, S.L. (2006) Endoplasmic reticulum stress in health and disease. Curr. Opin. Cell. Biol. 18, 444–452.[CrossRef][Medline]
Zhong, X., Shen, Y., Ballar, P., Apostolou, A., Agami, R. & Fang, S. (2004) AAA ATPase p97/valosin-containing protein interacts with gp78, a ubiquitin ligase for endoplasmic reticulum-associated degradation. J. Biol. Chem. 279, 45676–45684.
Accepted: 11 June 2007
This article has been cited by other articles:
|
|
 |
|
  N. Habibi-Babadi, A. Su, C. E. de Carvalho, and A. Colavita The N-Glycanase png-1 Acts to Limit Axon Branching during Organ Formation in Caenorhabditis elegans J. Neurosci., February 3, 2010; 30(5): 1766 - 1776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Morck, L. Olsen, C. Kurth, A. Persson, N. J. Storm, E. Svensson, J.-O. Jansson, M. Hellqvist, A. Enejder, N. J. Faergeman, et al. Statins inhibit protein lipidation and induce the unfolded protein response in the non-sterol producing nematode Caenorhabditis elegans PNAS, October 27, 2009; 106(43): 18285 - 18290. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sasagawa, M. Otani, N. Higashitani, A. Higashitani, K. Sato, T. Ogura, and K. Yamanaka Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner J. Cell Sci., October 15, 2009; 122(20): 3663 - 3672. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Dejima, D. Murata, S. Mizuguchi, K. H. Nomura, K. Gengyo-Ando, S. Mitani, S. Kamiyama, S. Nishihara, and K. Nomura The ortholog of human solute carrier family 35 member B1 (UDP-galactose transporter-related protein 1) is involved in maintenance of ER homeostasis and essential for larval development in Caenorhabditis elegans FASEB J, July 1, 2009; 23(7): 2215 - 2225. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | ADVANCED SEARCH | TABLE OF CONTENTS |
