Ubiquitination regulates the assembly of VLDL in HepG2 cells and is the committing step of the apoB-100 ERAD pathway

Apolipoprotein B-100 (apoB-100) is degraded by endoplasmic reticulum-associated degradation (ERAD) when lipid availability limits assembly of VLDLs. The ubiquitin ligase gp78 and the AAA-ATPase p97 have been implicated in the proteasomal degradation of apoB-100. To study the relationship between ERAD and VLDL assembly, we used small interfering RNA (siRNA) to reduce gp78 expression in HepG2 cells. Reduction of gp78 decreased apoB-100 ubiquitination and cytosolic apoB-ubiquitin conjugates. Radiolabeling studies revealed that gp78 knockdown increased secretion of newly synthesized apoB-100 and, unexpectedly, enhanced VLDL assembly, as the shift in apoB-100 density in gp78-reduced cells was accompanied by increased triacylglycerol (TG) secretion. To explore the mechanisms by which gp78 reduction might enhance VLDL assembly, we compared the effects of gp78 knockdown with those of U0126, a mitogen-activated protein kinase/ERK kinase1/2 inhibitor that enhances apoB-100 secretion in HepG2 cells. U0126 treatment increased secretion of both apoB100 and TG and decreased the ubiquitination and cellular accumu­lation of apoB-100. Furthermore, p97 knockdown caused apoB-100 to accumulate in the cell, but if gp78 was concomitantly reduced or assembly was enhanced by U0126 treatment, cellular apoB-100 returned toward baseline. This indicates that ubiquitination commits apoB-100 to p97-mediated retrotranslocation during ERAD. Thus, decreasing ubiquitination of apoB-100 enhances VLDL assembly, whereas improving apoB-100 lipidation decreases its ubiquitination, suggesting that ubiquitination has a regulatory role in VLDL assembly. Apolipoprotein B-100 (apoB-100) is degraded by endoplasmic reticulum-associated degradation (ERAD) when lipid availability limits assembly of VLDLs. The ubiquitin ligase gp78 and the AAA-ATPase p97 have been implicated in the proteasomal degradation of apoB-100. To study the relationship between ERAD and VLDL assembly, we used small interfering RNA (siRNA) to reduce gp78 expression in HepG2 cells. Reduction of gp78 decreased apoB-100 ubiquitination and cytosolic apoB-ubiquitin conjugates. Radiolabeling studies revealed that gp78 knockdown increased secretion of newly synthesized apoB-100 and, unexpectedly, enhanced VLDL assembly, as the shift in apoB-100 density in gp78-reduced cells was accompanied by increased triacylglycerol (TG) secretion. To explore the mechanisms by which gp78 reduction might enhance VLDL assembly, we compared the effects of gp78 knockdown with those of U0126, a mitogen-activated protein kinase/ERK kinase1/2 inhibitor that enhances apoB-100 secretion in HepG2 cells. U0126 treatment increased secretion of both apoB100 and TG and decreased the ubiquitination and cellular accumu­lation of apoB-100. Furthermore, p97 knockdown caused apoB-100 to accumulate in the cell, but if gp78 was concomitantly reduced or assembly was enhanced by U0126 treatment, cellular apoB-100 returned toward baseline. This indicates that ubiquitination commits apoB-100 to p97-mediated retrotranslocation during ERAD. Thus, decreasing ubiquitination of apoB-100 enhances VLDL assembly, whereas improving apoB-100 lipidation decreases its ubiquitination, suggesting that ubiquitination has a regulatory role in VLDL assembly. Apolipoprotein (apo) B-100 is the major protein component of VLDLs. Assembly of VLDL in the liver begins at the endoplasmic reticulum (ER) with the formation of a primordial lipoprotein. As apoB-100 enters the ER lumen cotranslationally, it must associate with sufficient lipids for VLDL assembly to proceed. The microsomal triglyceride transfer protein (MTP) facilitates transfer of lipids onto nascent apoB-100 (1Shelness G.S. Ledford A.S. Evolution and mechanism of apolipoprotein B-containing lipoprotein assembly.Curr. Opin. Lipidol. 2005; 16: 325-332Crossref PubMed Scopus (87) Google Scholar). ApoB-100 is somewhat unique in that its secretion can be regulated by degradation (2Lapierre L.R. McLeod R.S. Regulation of hepatic production of lipoproteins containing apolipoprotein B by ER-associated degradation.Future Lipidol. 2007; 2: 173-184Crossref Scopus (3) Google Scholar), whereas control of expression of most proteins is at the level of mRNA transcription or translation. During conditions that limit lipid supply, such as low MTP activity (3Benoist F. Grand-Perret T. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer protein. Synchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein.J. Biol. Chem. 1997; 272: 20435-20442Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar) or reduced lipid availability (4Dixon J.L. Furukawa S. Ginsberg H.N. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B.J. Biol. Chem. 1991; 266: 5080-5086Abstract Full Text PDF PubMed Google Scholar, 5Zhou M. Fisher E.A. Ginsberg H.N. Regulated co-translational ubiquitination of apolipoprotein B100. A new paradigm for proteasomal degradation of a secretory protein.J. Biol. Chem. 1998; 273: 24649-24653Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar), apoB-100 is delivered to and degraded by the cytosolic proteasome in a process termed ER-associated degradation (ERAD). ApoB-100 contains large hydrophobic regions that require lipidation during apoB-100 synthesis or the nascent protein is targeted to ERAD (6Lapierre L.R. Currie D.L. Yao Z. Wang J. McLeod R.S. Amino acid sequences within the β1 domain of human apolipoprotein B can mediate rapid intracellular degradation.J. Lipid Res. 2004; 45: 366-377Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In a process that remains poorly defined, apoB-100 can be secreted only if lipidation/assembly satisfies the quality control surveillance system in the secretory pathway. The ERAD pathway removes malfolded proteins from the ER lumen or membrane [reviewed in (7Vembar S.S. Brodsky J.L. One step at a time: endoplasmic reticulum-associated degradation.Nat. Rev. Mol. Cell Biol. 2008; 9: 944-957Crossref PubMed Scopus (1019) Google Scholar)]. ERAD helps reduce the burden on ER-resident chaperones and allows the cell to maintain ER homeostasis. The typical ERAD pathway for a protein in the secretory pathway consists of at least the following steps: substrate recognition, retrotranslocation from the ER into the cytosol and ubiquitination, followed by degradation in the proteasome. These steps require cooperation between luminal chaperones, integral membrane proteins, cytosolic chaperones, and the proteasome. Some of these ERAD components have been implicated in the proteasomal degradation of apoB-100 (8Rutledge A.C. Su Q. Adeli K. Apolipoprotein B100 biogenesis: a complex array of intracellular mechanisms regulating folding, stability, and lipoprotein assembly.Biochem. Cell Biol. 2010; 88: 251-267Crossref PubMed Scopus (72) Google Scholar). During apoB-100 biogenesis, competition between lipidation and the degradative machinery may govern the level of VLDL secretion (9Sakata N. Wu X. Dixon J.L. Ginsberg H.N. Proteolysis and lipid-facilitated translocation are distinct but competitive processes that regulate secretion of apolipoprotein B in Hep G2 cells.J. Biol. Chem. 1993; 268: 22967-22970Abstract Full Text PDF PubMed Google Scholar). When lipidation is insufficient to support VLDL assembly, the cotranslational entry of apoB into the ER lumen through the Sec61 translocon is delayed, causing portions of the newly synthesized apoB to become cytosolically exposed (10Mitchell D.M. Zhou M. Pariyarath R. Wang H. Aitchison J.D. Ginsberg H.N. Fisher E.A. Apoprotein B100 has a prolonged interaction with the translocon during which its lipidation and translocation change from dependence on the microsomal triglyceride transfer protein to independence.Proc. Natl. Acad. Sci. USA. 1998; 95: 14733-14738Crossref PubMed Scopus (109) Google Scholar). This 'translocation arrest’ gives nascent apoB-100 a bitopic topology, defined as simultaneous exposure to the cytosol and ER lumen. It is possible that this unique conformation initiates the ERAD of apoB-100 but it is unclear what factor(s) are necessary and sufficient for substrate recognition. On one hand, poor apoB lipidation could create exposed hydrophobic domains in the ER lumen that attract specific chaperones, whereas on the other hand, cytosolic exposure of newly translated apoB-100 epitopes may interaction with cytosolic components of the ERAD Furthermore, through the translocon may to of ERAD as The ER protein protein with nascent apoB-100 when the interaction between MTP and apoB-100 is A.C. R. R. N. Adeli K. apolipoprotein B100 to proteasomal that degradation is by at the and the formation of a p97 complex at the Biol. PubMed Scopus Google Scholar). with may of a poorly apoB It has been by E.A. L.R. McLeod R.S. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) and by A.C. R. R. N. Adeli K. apolipoprotein B100 to proteasomal that degradation is by at the and the formation of a p97 complex at the Biol. PubMed Scopus Google Scholar) that the with cellular p97 is in the of apoB-100 from the ER into the cytosol and facilitates its proteasomal of the cytosolic protein and M. Wu X. Ginsberg H.N. Apoprotein an secretory is to the cytosolic protein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Brodsky J.L. Fisher E.A. Apoprotein B degradation is by the chaperones and Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), have in apoB-100 These chaperones may maintain cytosolic in an that is for proteasomal of the ubiquitin ligase as in HepG2 cells increased apoB-100 ubiquitination and degradation decreasing apoB-100 secretion T. S. J. Fisher E.A. Ginsberg H.N. of the a ubiquitin protein in increased and decreased secretion of apolipoprotein B100 in HepG2 cells.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). To this is the only ubiquitin ligase implicated in the ERAD pathway of apoB-100. can with p97 a to a complex that retrotranslocation and ubiquitination of from the ER for degradation X. R. S. protein with a ubiquitin ligase for endoplasmic reticulum-associated degradation.J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). This to the relationship between gp78 and p97 in apoB-100 ERAD. In the HepG2 cell apoB-100 secretion is by of lipids to the of VLDL assembly. As a the of lipoprotein secreted from HepG2 cells is in the the VLDL secreted by Furthermore, a large of nascent apoB-100 is from the secretory pathway and degraded by ERAD. it was that the VLDL assembly in HepG2 cells could be by inhibiting the U0126 J. R. Adeli K. the in VLDL assembly in HepG2 role of in Biol. 2007; PubMed Scopus Google Scholar). The mechanism is In this we the relationship between enhanced VLDL assembly, p97-mediated and ubiquitination on the and secretion of apoB-100 in HepG2 cells. HepG2 cells from the in in with by at cells onto or small interfering cells in a with treated with or with or U0126 by to and by with to apoB ubiquitin p97 protein protein and or from from of a was containing or one of or and to a of HepG2 at and in low in cells to the in to a of and of The was with and following The of the knockdown was by of cell for p97 protein and by for the gp78 mRNA RNA was from HepG2 cells with the transcription for RNA was as RNA and of and to with and for at and to for to this and for a of at for for and to the of the of the and and was to with at for for and to was by the between to as a HepG2 cells in at in for and for to on the in containing of cells with acid or during the and U0126 or through of apoB-100 synthesis and the was and the cells by as of apoB and the was a and the with containing and and by in a containing as (6Lapierre L.R. Currie D.L. Yao Z. Wang J. McLeod R.S. Amino acid sequences within the β1 domain of human apolipoprotein B can mediate rapid intracellular degradation.J. Lipid Res. 2004; 45: 366-377Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Cell and to and apoB protein was by with a to human apoB on protein A and into ApoB-100 was by and by was from by A to human was used to HepG2 by on of HepG2 cells in with or for on McLeod R.S. Yao Z. Adeli K. translocation and of apolipoprotein B are to the of the nascent Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). and membrane by in as HepG2 cells in the or of for the cells with and cytosol and membrane to and apoB was by with to human apoB and protein A as in containing the apoB was by to and with to apoB or was from HepG2 to and a was as R.S. Wang Wang S. Yao Z. Apolipoprotein B for hepatic low density lipoprotein Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). for at in a of and of apoB-100 as HepG2 cells with U0126 or with to for with and with U0126 and cell in Lipid was by and lipids by on for and as lipid McLeod R.S. Yao Z. activity of microsomal triglyceride transfer protein is for the secretion of low density lipoproteins containing apolipoprotein B from cells.J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). with TG and and was by HepG2 cells with and to cytosol cells on and for with the of in inhibitor was to a of Cell and of apoB-100 and as To the relationship between gp78 and apoB-100 we used an RNA to reduce gp78 expression in HepG2 cells. It has been that of gp78 in HepG2 cells enhances apoB-100 ubiquitination and decreases apoB-100 secretion T. S. J. Fisher E.A. Ginsberg H.N. of the a ubiquitin protein in increased and decreased secretion of apolipoprotein B100 in HepG2 cells.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with a control or for mRNA and protein To the of the RNA was from the cells for mRNA in the cells was reduced by compared with when to mRNA revealed of gp78 protein gp78 is an its expression might protein in the this the ER caused by protein might an protein the of which is increased expression K. to the 2008; PubMed Scopus Google Scholar). was by the gp78 knockdown suggesting that ER was the cytosolic was that cytosolic J. and Full Text Full Text PDF PubMed Scopus Google Scholar) was by the gp78 knockdown was p97 expression the knockdown of gp78 the level of apoB-100 in HepG2 cells as by To the role of gp78 in apoB cells with or gp78 treated with the proteasome inhibitor for to one with apoB in the apoB as a with an In the cells with gp78 apoB suggesting that gp78 expression is for the of apoB-ubiquitin conjugates. These T. S. J. Fisher E.A. Ginsberg H.N. of the a ubiquitin protein in increased and decreased secretion of apolipoprotein B100 in HepG2 cells.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) gp78 increased the ubiquitination of apoB in HepG2 cells. was used to cytosolic apoB with or gp78 As in the of the of apoB was in the membrane to the cytosolic treatment of cells with apoB-ubiquitin in both the membrane and cytosol with the only in the cytosol In to the gp78-reduced cells apoB-ubiquitin in the cytosol and apoB-100 proteins in the membrane This that gp78 ubiquitination and to the production of apoB-ubiquitin in the In treated the apoB-ubiquitin by could be translated apoB-100 To explore we apoB-100 synthesis of cells of caused the of apoB in cells compared with at In in gp78-reduced the of apoB was with or This that cotranslational of apoB to ERAD gp78 To the of reduced gp78 expression on newly synthesized we intracellular and secretion for with and cells and a and for of apoB-100 and In the gp78-reduced apoB-100 secretion was increased by the cells but apoB-100 was increased by gp78 of was by the that the secretory pathway was that the in apoB-100 secretion might the production of poorly lipoproteins that To the of gp78 knockdown on VLDL assembly, was by density and apoB-100 was from we a shift in the secretion in gp78 knockdown cells compared with control cells gp78 expression increased the apoB-100 in The shift in lipoprotein density was with a gp78 that the enhanced VLDL assembly was an of that It that when gp78 expression was the apoB protein could lipid control the decreased density of the secreted lipoproteins is of an increased revealed that triglyceride secretion was increased by the gp78 knockdown in the of acid triglyceride synthesis from was reduced in cells but this TG secretion. gp78 reduction the of proteins in lipid regulatory protein and It has been that a of the cellular apoB-100 is cytosolically exposed as it through the secretory pathway assembly of low density of of the endoplasmic reticulum of Biol. Chem. Full Text PDF PubMed Google Scholar, J. Adeli K. in apolipoprotein B intracellular assembly and degradation of lipoprotein in HepG2 Biol. 1997; PubMed Google Scholar). The of cytosolic exposure of apoB-100 could its to that reduced ubiquitination might the cytosolic exposure of apoB-100. To and cells to proteins within the microsomal and membrane The of was in both and cells ApoB-100 was to but apoB-100 was in in cells A revealed of apoB-100 with when to This that reduced gp78 expression the membrane of apoB-100. As J. R. Adeli K. the in VLDL assembly in HepG2 role of in Biol. 2007; PubMed Scopus Google Scholar), we that the inhibitor U0126 the apoB-100 density in a from to VLDL when cell was by To the secretion of cellular cells with for followed by and of from the cells and U0126 of into cellular whereas acid a large in cellular of into the was by U0126 or and was a on secretion when U0126 and acid these that the in cellular with acid secretion but the of U0126 the of into on the of VLDL formation in gp78 knockdown cells and with U0126 treatment, we that apoB-100 could ubiquitination and degradation in cells the that ERAD was When and U0126 nascent apoB with suggesting that U0126 reduced apoB-100 ERAD apoB-100 secretion was increased by U0126 but on apoB-100 secretion As in U0126 and or apoB-100 during a compared with the U0126 increased apoB-100 secretion whereas U0126 apoB-100 synthesis the enhanced secretion to apoB-100 that ERAD during conditions of lipid the reduced cellular apoB-100 and increased secretion that by U0126 reduced the entry of newly synthesized apoB into the ERAD pathway by an that VLDL assembly. that cells apoB following the This that in these cells apoB-100 could from the ERAD pathway at a step The in apoB was accompanied by a reduction in ubiquitination in cells The of apoB-100 from the ER into the cytosol for proteasomal degradation is by p97 A.C. R. R. N. Adeli K. apolipoprotein B100 to proteasomal that degradation is by at the and the formation of a p97 complex at the Biol. PubMed Scopus Google Scholar, E.A. L.R. McLeod R.S. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). and p97 are to associate with one and the ubiquitination and retrotranslocation of other ERAD S. Regulation of ER-associated degradation 2008; PubMed Scopus Google Scholar). of p97 the of nascent causing it to accumulate E.A. L.R. McLeod R.S. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). that if gp78 and p97 in the apoB ERAD ubiquitination may p97-mediated retrotranslocation and if gp78 knockdown in cells the apoB and enhance secretion. Furthermore, U0126 reduce apoB in cells apoB could be from ERAD ubiquitination, the cells for in the of the p97 knockdown caused apoB-100 to control cells the knockdown of both p97 and gp78 caused of nascent apoB-100 U0126 the on apoB-100 as gp78 knockdown when the p97 knockdown gp78 knockdown and U0126 to enhance apoB-100 secretion from p97 knockdown cells U0126, gp78 knockdown suggesting that the effects of gp78 and U0126 treatment are study E.A. L.R. McLeod R.S. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar) an in with p97 with a ER and this was both gp78 knockdown and U0126 treatment decreased the in cells. These that ubiquitination or assembly can reduce the apoB and ER in cells. The has revealed an role for the ubiquitin ligase gp78 in the of apoB-100. knockdown in a gp78 study T. S. J. Fisher E.A. Ginsberg H.N. of the a ubiquitin protein in increased and decreased secretion of apolipoprotein B100 in HepG2 cells.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) to that gp78 is a ubiquitin ligase that apoB-100 ERAD. In decreasing the ubiquitination of apoB-100 can enhance VLDL assembly, it a new level of in the relationship between apoB secretion and ERAD. studies the inhibitor U0126 have that this by the of of new TG synthesis to VLDL assembly in HepG2 cells. knockdown that ubiquitination of apoB-100 in HepG2 cells the of p97 and is the step for ERAD. Thus, poorly or apoB-100 are ERAD but apoB These to the new that of VLDL assembly in may be on a ERAD pathway. that a of HepG2 apoB-100 that be degraded by the ERAD pathway can through the secretory pathway to a when ubiquitination or lipidation is ubiquitination gp78 and lipid inhibiting with both enhanced the secretion of apoB-100 and lipids cellular apoB-100 U0126 ubiquitination, and gp78 knockdown or the expression of proteins to regulate VLDL secretion lipid and To the only between the gp78 knockdown and U0126 are the effects on apoB-100 ubiquitination and VLDL secretion. The ERAD pathway a large of nascent apoB and this can when ubiquitination is enhanced T. S. J. Fisher E.A. Ginsberg H.N. of the a ubiquitin protein in increased and decreased secretion of apolipoprotein B100 in HepG2 cells.J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). reduction of apoB ubiquitination enhances assembly, apoB could be for ERAD on during or translation and, as a assembly at these that ERAD and VLDL may be In gp78 knockdown newly synthesized apoB-100 was to the cytosol and secretion of both apoB-100 and TG suggesting that ubiquitination both the of apoB-100 and lipid during VLDL ubiquitin is onto a cytosolic of the apoB-ubiquitin could translocation through the Sec61 of ubiquitination may apoB-100 to prolonged exposure to the cytosol and the of translocation and VLDL assembly. The ERAD paradigm that of malfolded protein to the of ubiquitin ligase K. Brodsky J.L. The and retrotranslocation of proteins from the endoplasmic 2008; 9: PubMed Scopus Google Scholar). U0126 treatment enhances of TG into VLDL and in may apoB to translocation and ERAD at the substrate lipidation and decreased cytosolic exposure to increased translocation when apoB ERAD. the and of the of its unique exposure to the cytosol during assembly, may require the and retrotranslocation steps by most ERAD ubiquitination (7Vembar S.S. Brodsky J.L. One step at a time: endoplasmic reticulum-associated degradation.Nat. Rev. Mol. Cell Biol. 2008; 9: 944-957Crossref PubMed Scopus (1019) Google Scholar). poorly apoB-100 is it to be to with the that support VLDL assembly, ERAD substrate a regulatory role for ubiquitination in VLDL assembly. During biogenesis, a of the nascent apoB-100 may in an ApoB-100 contains hydrophobic domains that to lipids Wang J. McLeod R.S. D.M. study of a that can apoB to lipoproteins and it Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). the quality control surveillance machinery is with the of these it that apoB-100 must to the ERAD pathway. ApoB-100 with the membrane during of assembly and is into the lumen during VLDL J.L. R. T. of of nascent and apoB in the endoplasmic reticulum of Cell Biol. PubMed Scopus Google Scholar, K. M. J. assembly and degradation of apolipoprotein lipoproteins in G2 cells.J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), with in apoB in the J. Brodsky J.L. Fisher E.A. of low density lipoproteins in apolipoprotein but is on apolipoprotein Biol. Chem. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). apoB-100 has been in translation has been but the step X. J.D. Dixon J.L. of regions in apolipoprotein B100 that are exposed on the cytosolic of the endoplasmic reticulum Cell Biol. 1998; PubMed Scopus Google Scholar). of apoB-100 into the lumen during may apoB from to ERAD. of ubiquitination that ERAD but can be or on quality control When p97 is apoB-100 proteins become at the ER membrane to retrotranslocation E.A. L.R. McLeod R.S. The AAA-ATPase p97 facilitates degradation of apolipoprotein B by the Lipid Res. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). The apoB-100 the assembly acid during apoB-100 secretion from cells apoB-100 can become if ERAD is at the or ubiquitination step and gp78 U0126 and gp78 knockdown cellular apoB-100 in that the ubiquitination of apoB-100 is the step of ERAD and that p97-mediated retrotranslocation is an integral membrane protein that can as a for the assembly of protein that the ERAD of S. Regulation of ER-associated degradation 2008; PubMed Scopus Google Scholar). can to and p97 to the of the ER membrane X. R. S. protein with a ubiquitin ligase for endoplasmic reticulum-associated degradation.J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). It is possible that decreased gp78 expression the of ERAD p97 and other at the ER it was that the of the protein the domain of gp78 and the but the of gp78 to the protein H. S. S. with the domain of gp78 and gp78 to ubiquitin and 2010; PubMed Scopus Google Scholar). This that the ligase activity of gp78 on the formation of a ERAD the gp78 and p97 have on apoB-100 ubiquitination of apoB-100 is the of increased apoB-100 secretion in gp78-reduced cells. The of ER in gp78-reduced cells may to the knockdown or may that other ubiquitin can for decreased gp78 The knockdown of p97 expression to on knockdown and cell M. M. protein is a of endoplasmic reticulum and of the degradation of and degradation pathway in Biol. PubMed Scopus Google Scholar, of the complex in the regulated endoplasmic reticulum-associated degradation of Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar), of in the endoplasmic reticulum protein Rev. Mol. Cell Biol. 2007; PubMed Scopus Google Scholar). In this to be as it protein a of or the synthesis or secretion of apoB-100 or of have been to the of apoB-100 T. Ginsberg H.N. of apolipoprotein B100 secretion by hepatic endoplasmic reticulum in 2008; PubMed Scopus Google Scholar). When gp78 knockdown or U0126 treatment was with the p97 knockdown by apoB-100 through distinct gp78 knockdown and U0126 are to ER in cells. This that apoB-100 may be the major of the ER in p97 knockdown cells. it was that of the apoB-100 protein may be a between ER and hepatic Q. J. M. Adeli K. 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In that ubiquitination of apoB-100 has a regulatory role during VLDL assembly in HepG2 cells. gp78 and of p97 in the apoB-100 ERAD pathway. ubiquitination as the step of apoB-100 to which the nascent protein can to with apolipoprotein protein endoplasmic reticulum endoplasmic reticulum-associated degradation ubiquitin ligase protein mitogen-activated protein kinase/ERK microsomal triglyceride transfer protein acid small interfering RNA triacylglycerol protein protein

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