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ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N-glycanase

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Abstract

ER degradation-enhancing α-mannosidase-like 1 protein (EDEM1) is involved in the routing of misfolded glycoproteins for degradation in the cytoplasm. Previously, we reported that EDEM1 leaves the endoplasmic reticulum via non-COPII vesicles (Zuber et al. in Proc Natl Acad Sci USA 104:4407–4412, 2007) and becomes degraded by basal autophagy (Le Fourn et al. in Cell Mol Life Sci 66:1434–1445, 2009). However, it is unknown which type of autophagy is involved. Likewise, how EDEM1 is targeted to autophagosomes remains elusive. We now show that EDEM1 is degraded by selective autophagy. It colocalizes with the selective autophagy cargo receptors p62/SQSTM1, neighbor of BRCA1 gene 1 (NBR1) and autophagy-linked FYVE (Alfy) protein, and becomes engulfed by autophagic isolation membranes. The interaction with p62/SQSTM1 and NBR1 is required for routing of EDEM1 to autophagosomes since it can be blocked by short inhibitory RNA knockdown of the cargo receptors. Furthermore, p62/SQSTM1 interacts only with deglycosylated EDEM1 that is also ubiquitinated. The deglycosylation of EDEM1 occurs by the cytosolic peptide N-glycanase and is a prerequisite for interaction and aggregate formation with p62/SQSTM1 as demonstrated by the effect of peptide N-glycanase inhibitors on the formation of protein aggregates. Conversely, aggregation of p62/SQSTM1 and EDEM1 occurs independent of cytoplasmic histone deacetylase. These data provide novel insight into the mechanism of autophagic degradation of the ER-associated protein degradation (ERAD) component EDEM1 and disclose hitherto unknown parallels with the clearance of cytoplasmic aggregates of misfolded proteins by selective autophagy.

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Abbreviations

Alfy:

Autophagy-linked FYVE protein

BODY-(GlcNAc)2-CIAc:

Chloroacetamidyl chitobiose coupled to 4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-propionic acid

PNGase:

Cytoplasmic peptide N-glycanase

EDEM1:

ER degradation-enhancing α-mannosidase-like 1 protein

ER:

Endoplasmic reticulum

ERAD:

ER-associated protein degradation

LC3:

Microtubule-associated protein 1 light chain 3 beta

man:

Mannose

GlcNAc:

N-Acetylglucosamine

NBR1:

Neighbor of BRCA1 gene 1

p62/SQSTM1:

Sequestosome 1

siRNA:

Short inhibitory RNA

Z-VAD(OMe)-fmk:

Carbobenzyloxy-Val-Ala-Asp-α-fluoromethylketone

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Acknowledgments

We would like to thank Jon Soderholm (Yonsei University) for helpful comments on the manuscript. This work was supported by Korean Research WCU Grant R31-10086 (to J. R. and J. W. C.), the National Research Foundation of Korea by the Ministry of Education, Science and Technology (2010-0027736) (to J. R. and J. W. C.) and the Swiss National Science Foundation (to J. R.). Insook Jang is recipient of a fellowship from the Brain Korea 21 program.

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Authors and Affiliations

  1. WCU Program, Department of Integrated OMICS for Biomedical Science, Yonsei University Graduate School, Seoul, 120-749, Korea

    Sujin Park, Insook Jang, Yangsin Lee, Jin Won Cho & Jürgen Roth

  2. Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, 8091, Zurich, Switzerland

    Christian Zuber & Jürgen Roth

  3. Department of Chemistry and Chemical Biology, Gunma University, Maebashi, Gunma, 376-8515, Japan

    Ichiro Matsuo

  4. Synthetic Cellular Chemistry Laboratory, RIKEN, Wako, Saitama, 351-0198, Japan

    Yukishige Ito

  5. ERATO Glycotrilogy Project, JST, Wako, Saitama, 351-0198, Japan

    Yukishige Ito

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  1. Sujin Park
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  2. Insook Jang
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  3. Christian Zuber
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  4. Yangsin Lee
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  6. Ichiro Matsuo
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  7. Yukishige Ito
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  8. Jürgen Roth
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Corresponding author

Correspondence to Jürgen Roth.

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Sujin Park and Insook Jang have contributed equally to this work.

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Park, S., Jang, I., Zuber, C. et al. ERADication of EDEM1 occurs by selective autophagy and requires deglycosylation by cytoplasmic peptide N-glycanase. Histochem Cell Biol 142, 153–169 (2014). https://doi.org/10.1007/s00418-014-1204-3

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