Unknown

Dataset Information

0

N-terminal extension of the cholera toxin A1-chain causes rapid degradation after retrotranslocation from endoplasmic reticulum to cytosol.


ABSTRACT: Cholera toxin travels from the plasma membrane to the endoplasmic reticulum of host cells, where a portion of the toxin, the A1-chain, is unfolded and targeted to a protein-conducting channel for retrotranslocation to the cytosol. Unlike most retrotranslocation substrates, the A1-chain escapes degradation by the proteasome and refolds in the cytosol to induce disease. How this occurs remains poorly understood. Here, we show that an unstructured peptide appended to the N terminus of the A1-chain renders the toxin functionally inactive. Cleavage of the peptide extension prior to cell entry rescues toxin half-life and function. The loss of toxicity is explained by rapid degradation by the proteasome after retrotranslocation to the cytosol. Degradation of the mutant toxin does not follow the N-end rule but depends on the two Lys residues at positions 4 and 17 of the native A1-chain, consistent with polyubiquitination at these sites. Thus, retrotranslocation and refolding of the wild-type A1-chain must proceed in a way that protects these Lys residues from attack by E3 ligases.

SUBMITTER: Wernick NL 

PROVIDER: S-EPMC2825409 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

altmetric image

Publications

N-terminal extension of the cholera toxin A1-chain causes rapid degradation after retrotranslocation from endoplasmic reticulum to cytosol.

Wernick Naomi L B NL   De Luca Heidi H   Kam Wendy R WR   Lencer Wayne I WI  

The Journal of biological chemistry 20100107 9


Cholera toxin travels from the plasma membrane to the endoplasmic reticulum of host cells, where a portion of the toxin, the A1-chain, is unfolded and targeted to a protein-conducting channel for retrotranslocation to the cytosol. Unlike most retrotranslocation substrates, the A1-chain escapes degradation by the proteasome and refolds in the cytosol to induce disease. How this occurs remains poorly understood. Here, we show that an unstructured peptide appended to the N terminus of the A1-chain  ...[more]

Similar Datasets

| S-EPMC2951200 | biostudies-literature
| S-EPMC2950133 | biostudies-other
| S-EPMC4030972 | biostudies-literature
| S-EPMC3596249 | biostudies-other
2011-12-20 | E-GEOD-31539 | biostudies-arrayexpress
2011-12-20 | GSE31539 | GEO
| S-EPMC1618096 | biostudies-literature
| S-EPMC2175082 | biostudies-literature
| S-EPMC3487549 | biostudies-literature
| S-EPMC5116717 | biostudies-literature