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Biochim Biophys Acta. 2011 Aug;1810(8):790-8. doi: 10.1016/j.bbagen.2011.04.017. Epub 2011 May 12.

ER-stress-inducible Herp, facilitates the degradation of immature nicastrin.

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1
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Fukuoka 812-8581, Japan.

Abstract

BACKGROUND:

Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein harboring an ubiquitin-like domain (ULD). However, its biological functions are not fully understood. Here, we examined the role of Herp in the degradation of γ-secretase components.

METHODS:

Effects of ULD-lacking Herp (ΔUb-Herp) expression on the degradation of γ-secretase components were analyzed.

RESULTS:

The cellular expression of ΔUb-Herp was found to inhibit the degradation of overexpressed immature nicastrin and full-length presenilin. The mechanisms underlying Herp-mediated nicastrin degradation was further analyzed. We found that immature nicastrin accumulates in the ER of ΔUb-Herp overexpressing cells or Herp-deficient cells more than that in the ER of wild-type cells. Further, ΔUb-Herp expression inhibited nicastrin ubiquitination, suggesting that the ULD of Herp is likely involved in nicastrin ubiquitination. Co-immunoprecipitation study showed that Herp as well as ΔUb-Herp potentially interacts with nicastrin, mediating nicastrin interaction with p97, which functions in retranslocation of misfolded proteins from the ER to the cytosol.

CONCLUSIONS:

Thus, Herp is likely involved in degradation of immature nicastrin by facilitating p97-dependent nicastrin retranslocation and ubiquitination.

GENERAL SIGNIFICANCE:

We suggest that Herp could play a role in the elimination of the excess unassembled components of a multimeric complex.

PMID:
21600962
DOI:
10.1016/j.bbagen.2011.04.017
[Indexed for MEDLINE]
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