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ERAD substrates

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Definition:


Glycosylated:


Non-glycosylated:


Physiological ERAD substrates:

  • HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A)
    • HRD dependent substrate; absence of lectins (Yos9/OS-9/XTP3-B) does not affect its degradation
    • Hmg2p in yeast: rate-limiting enzyme in cholesterol synthesis; when cholesterol levels are high, Hmg2p undergoes lipid-induced structural change so that it resembles a misfolded protein --> targeted for degradation to Hrd1p (circumvents need for adaptor proteins such as Usa1p, Der1p or Yos9p)
    • mammalian HMG-CoA reductase: also regulated via degradation
  • Apolipoportein B (apoB):
    • involved in delivery of cholesterol to tissues
    • co-translationally degraded if not adequately loaded with cargo (Brodsky & Fisher, 2008; Trends Endocrinol Metab)
  • Erg3p: component of sterol biosynthesis pathway in yeast; also endogenous ERAD substrate


ERAD substrates

in yeast:

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· CPY*

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Figure 1. Involvement of ERAD components in CPY* (Hosomi, 2010)

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· 'RTL' (Hosomi et al., 2010; JBC)

o membrane protein that consists of a luminal RTA (ricin A chain non-toxic mutant; a mutant plant toxin protein);

o RTA has two potential N-glycosylation sites: N10 and N236 à N10 is the primary glycosylation site

• type I transmembrane domain of Pdr5

• cytoplasmic Leu2 protein

o (similar to CTL*, which is the membrane version of CPY*)

o using this system, the efficiency of RTL degradation in yeast can be measured by growth of cells in synthetic media containing limited amount of leucine

o is degraded (as RTA) in a Png1-dependent fashion

o RTL lacking the first glycosylation site (RTLN10Q) did not require Png1 for efficient degradation à indicates that effect of Png1 is N-glycan dependent

o Der1, but not Sec61, seems to be essential for RTL degradation

o other proteins important for efficient RTL degradation included Hrd1 and Hrd3, typical components of the ERAD-L pathway; while components of the ERAD-C pathway, like Doa10 and Ufd2, were not required

o RTL stabilization was also observed in htm1 and yos9 KO cells; this effect was glycan-dependent, as non-glycosylated RTLN10Q was not stabilized in htm1 and yos9 KO cells

o interestingly, RTL and RTA stabilization was not observed in mns1 KO cells, while CPY* and CTL* both require Htm1, Yos9 and Mns1 for efficient degradation à only Htm1 function is needed for degradation of RTL/RTA, but not Mns1; Htm1 alone is capable of creating a M8C structure è essentiality of Mns1 on ERAD is substrate-specific!

o other proteins required for RTL degradation: Ubc7/Cue1, Ubx2, Usa1

o RTA degradation also requires functional ER-Golgi transport, as a sec18-1 mutant (Sec18 = homolog of mammalian N-ethylmaleimide (NEM)-sensitive fusion protein (NSF)) stabilizes the ERAD substrate

o degradation of RTA and RTL is not dependent on function Sec61, but instead depends on Der1, a putative component of the retro-translocation channel (previous studies with ricin A suggested the exact opposite, but apparently the less toxic version RTA needs Der1 instead of Sec61)

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in mammals:

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· A1AT wt: α1-antitrypsin: 394 aa, 3 N-glycans, plasma protein belonging to the serine protease inhibitor superfamily, lack of A1AT in the serum causes emphysema or liver cirrhosis

· A1AT NHK

o α1-antitrypsin null Hong Kong

o soluble, 3 N-glycosylation sites

o terminally misfolded in the ER and degraded by ERAD (Liu et al., 1999; JBC; Hosokawa et al., 2001; EMBO Rep)

o stabilized by:

§ knockdown of SEL1L, Hrd1 and OS-9 (Christianson et al., 2008; Nat Cell Biol)

§ treatment of cells with α1,2-mannosidase inhibitors (Liu, 1999)

§ proteasome inhibitors (MG132, lactacystin)

o accelerated degradation by:

§ overexpression of EDEM1 (Hosokawa et al., 2001; EMBO Reports)

§ overexpression of EDEM2 (Mast et al., 2005; Glycobiol)

§ overexpression of EDEM3 (Hirao et al., 2006; JBC)

§ overexpression of ERManI (à halflife of NHK with co-transfected ERManI is reduced from ~100 min to 50 min) à mannose trimming accelerated (kifunsensine inhibits NHK degradation in cells co-transfected with ERManI) (Hosokawa et al., 2003; JBC)

o in mock-transfected cells: major oligosaccharides on NHK were Glc1Man9 (à consistent with association of NHK with CNX!) and Man9 along with smaller amounts of Man8à during 4h chase mannose trimming was observed to Man7, Man6 and even Man5 by endogenous α1,2-mannosidase activity; overexpression of ERManI caused large increase in Man8 and appearance of Glc1Man8, an increase in Man5-7 and a decrease in Glc1Man9 and Man9; overexpression of EDEM: major oligosaccharides were Glc1Man9 and Man9 with smaller portions of Man6-8 (Hosokawa et al., 2003; JBC)

o NHK associates with calnexin (Le et al., 1994; JBC)

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Figure 2. NHK degradation upon different knock-downs (Christianson, 2008)

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Figure 3. Effect of kifunensine on oligosaccharides on misfolded NHK.

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· A1AT NHK-QQQ

o NHK lacking all 3 N-glycans (Asns replaced by Glns)

o also ERAD substrate, but degradation not accelerated by EDEM3 overexpression (Hirao et al., 2006; JBC)

o NHK-QQQ is degraded faster than NHK

o

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· A1AT PI Z

    • degradation occurs less quickly than NHK à could be because PIZ can spontaneously form loop-sheet polymers that may reduce the accessibility of protein monomers to be targeted for degradation (Lomas, 1992)
    • interacts with EDEM2 when HEK293 co-transfected with both (Mast et al., 2005; Glycobiol)
    • accelerated degradation by:

§ overexpression of EDEM2 (Mast et al., 2005; Glycobiol)

    • degradation of unglycosylated form is not accelerated by EDEM2 overexpression
    • retained in the ER, though some PI Z is able to be secreted from HEK293 cells (probably because a small portion is able to fold correctly) (Cabral et al., 2002; Mol Biol Cell)

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· TCRα

o glycosylated, transmembrane ERAD substrate

o T-cell receptor α-subunit

o unstable type I transmembrane protein

o knockdown of OS-9 or XTP3-B has no stabilizing effect on TCRα

o EDEM3 overexpression enhances degradation of TCRα (Hirao et al., 2006; JBC)

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· RI332

    • mutant of ribophorin I
    • ER lumenal ERAD substrate
    • knockdown of OS-9 or XTP3-B had no stabilizing effect on RI322

Figure 5. No stabilizing effect of OS-9 or XTP3-B knockdown (Christianson, 2008)

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· BACE457 (brain isoform of β-secretase (aspartyl protease): BACE501 à involved in generation of Alzheimer’s disease amyloid deposits; not misfolded!)

    • tetraglycosylated splice variant of human β-secretase (isoform expressed in the human pancreas); type I transmembrane glycoprotein
    • BACE467 originate from alternative splicing of BACE transcript, resulting in a 25aa deletion in the protein‘s luminal ectodomain à prevents attainment of native structure when ectopically expressed in cultured mammalian cells (Molinari et al., 2002; JCB)
    • degradation requires extensive de-mannosylation and is performed in the cytosol upon P97-facilitated extraction by 26S proteasomes (Molinari et al., 2002; JCB)
    • degradation starts in HEK293 control cells after lag phase of ~90 min; half life ~4h; upon EDEM upregulation lag phase is shortened to >30 min and half life to >90 min (Molinari et al., 2003; Science)
    • associates with calnexin and forms intramolecular disulfide bonds while folding (Molinari et al., 2003; Science)
    • degradation delayed in cells with low content of EDEM proteins (Molinari et al., 2003; Science)

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· BACE457Δ = soluble variant

o HRD1 pathways required for degradation (in contrast to the membrane-tethered BACE476) (Bernasconi et al., 2010; JCB)

o folding incompetent glycoprotein (used e.g. in Molinari et al., 2003; Science; and Molinari et al., 2002; JCB)

o half life in wt MEF cells: 45 min; degradation delayed in Xbp1-/- MEF cells (half life: 105 min) but degradation not completely blocked; slow degradation in Xbp1-/- cells can be accelerated again by overexpression of EDEM1

o half life in HEK293 control cells: ~45 min; upon EDEM upregulation shortened to >30 min (Molinari et al., 2003; Science)

o

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· BACE457ΔNOG

o folding incompetent non-glycosylated protein (used e.g. in Molinari et al., 2003; Science)

o degradation not affected by EDEM overexpression è EDEM upregulation only accelerates degradation of glycosylated membrane-bound & soluble ER substrates (Molinari et al., 2003; Science)

o

Figure 6. Consequences of Xbp1 depletion on ERAD (Eriksson, 2004)

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· BACE476

o BACE476 remains virtually constant in HEK293 cells for about 60 min (only 5% degraded); EDEM1 or EDEM2 overexpression accelerates degradation (32% and 27% degraded after 60 min) and release from CNX (Olivari et al., 2005; JBC)

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· BACE476NOG

    • BACE476 without N-glycans
    • rapidly degraded in HEK293 cells (in contrast to glycosylated BACE476, which remains virtually constant in HEK293 cells for about 60 min)
    • overexpression of EDEM1 or EDEM2 did not affect degradation of the non-glycosylated BACE (Olivari et al., 2005; JBC)

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in plants:

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· BRI1-5

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· MLO-1

    • plant-specific barley (Hordeum vulgare) seven-transmembrane domain mildew resistance o (MLO) protein à single amino acid substitution generates substrate for postinsertional quality control process in plants (Müller et al., 2005; Plant Cell)
    • mutant MLO protein is stabilized in yeast cells carrying defects in protein QC
    • MLO degradation is mediated by HRD pathway-dependent ERAD
    • in plants: abberant MLO protein exhibits markedly reduced half-life, is polyubiquitinated and can be stabilized by inhibition of proteasome activity
    • MLO accumulates at low levels in the plasma mebmran; N-terminus extracellularly, C-terminus intracellularly; Barley MLO interacts with Ca2+ sensor calmodulin and appears to inhibit a vesicle-associated and soluble NSF attachment protein receptor protein-dependent resistance reaction to the widespread powdery mildew pathogen Blumeria graminis f. sp hordei
    • MLO-1:3xHA ~80 kDa (with C-terminal degradation products from 30 to 50 kDa (Müller et al., 2005; Plant Cell)

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o Bernasconi, Riccardo, Carmela Galli, Verena Calanca, Toshihiro Nakajima, and Maurizio Molinari. 2010. “Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates.” The Journal of cell biology 188 (2) (January): 223-35. doi:10.1083/jcb.200910042. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2812524&tool=pmcentrez&rendertype=abstract.

o Cabral Christoph M., Liu Yan, Moremen Kelley W., Sifers Richard N. 2002. Mol Biol Cell:13:2639-2650

o Christianson, John C, Thomas A Shaler, Ryan E Tyler, and Ron R Kopito. 2008. “OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.” Nature Cell biology 10 (March): 272-282. doi:10.1038/ncb1689.

o Hirao K, Natsuka Y, Tamura T, Wada I, Morito D, Natsuka S, et al. EDEM3, a soluble EDEM homolog, enhances glycoprotein ERAD and mannose trimming. J Biol Chem 2006;281:9650.

o Hosokawa, N, I Wada, K Hasegawa, T Yorihuzi, L O Tremblay, a Herscovics, and K Nagata. 2001. “A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation.” EMBO reports 2 (5) (May): 415-22. doi:10.1093/embo-reports/kve084. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1083879&tool=pmcentrez&rendertype=abstract.

o Hosokawa, Nobuko, Linda O Tremblay, Zhipeng You, Annette Herscovics, Ikuo Wada, and Kazuhiro Nagata. 2003. “Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I.” The Journal of biological chemistry 278 (28) (July): 26287-94. doi:10.1074/jbc.M303395200. http://www.ncbi.nlm.nih.gov/pubmed/12736254.

o Hosomi, Akira, Kaori Tanabe, Hiroto Hirayama, Ikjin Kim, Hai Rao, and Tadashi Suzuki. 2010. “Identification of an Htm1 (EDEM)-dependent, Mns1-independent ERAD pathway in Saccharomyces cerevisiae.” The Journal of biological chemistry 285 (32) (June): 24324 -24334. doi:10.1074/jbc.M109.095919. http://www.ncbi.nlm.nih.gov/pubmed/20511219.

o Mast, Steven W, Krista Diekman, Khanita Karaveg, Ann Davis, Richard N Sifers, and Kelley W Moremen. 2005. “Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins.” Glycobiology 15 (4) (April): 421-36. doi:10.1093/glycob/cwi014. http://www.ncbi.nlm.nih.gov/pubmed/15537790.

o Molinari, Maurizio, Verena Calanca, Carmela Galli, Paola Lucca, and Paolo Paganetti. 2003. “Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.” Science (New York, N.Y.) 299 (5611) (February): 1397-400. doi:10.1126/science.1079474. http://www.ncbi.nlm.nih.gov/pubmed/12610306.

o Molinari, Maurizio, Carmela Galli, Verena Piccaluga, Michel Pieren, and Paolo Paganetti. 2002. “Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER.” The Journal of cell biology 158 (2) (July): 247-57. doi:10.1083/jcb.200204122. http://www.ncbi.nlm.nih.gov/pubmed/12119363.

o Müller, Judith, Pietro Piffanelli, Alessandra Devoto, Marco Miklis, Candace Elliott, Bodo Ortmann, Paul Schulze-Lefert, and Ralph Panstruga. 2005. “Conserved ERAD-Like Quality Control of a Plant Polytopic Membrane Protein.” The Plant Cell 17 (January): 149-163. doi:10.1105/tpc.104.026625.1.

o Olivari, Silvia, Carmela Galli, Heli Alanen, Lloyd Ruddock, and Maurizio Molinari. 2005. “A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation.” The Journal of biological chemistry 280 (4) (January): 2424-8. doi:10.1074/jbc.C400534200. http://www.ncbi.nlm.nih.gov/pubmed/15579471.

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