Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44

Alessandro Fraldi, Ester Zito, Fabio Annunziata, Alessia Lombardi, Marianna Cozzolino, Maria Monti, Carmine Spampanato, Andrea Ballabio, Piero Pucci, Roberto Sitia, Maria Pia Cosma

Research output: Contribution to journalArticle

Abstract

Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion.

Original languageEnglish
Pages (from-to)2610-2621
Number of pages12
JournalHuman Molecular Genetics
Volume17
Issue number17
DOIs
Publication statusPublished - 2008

ASJC Scopus subject areas

  • Genetics

Fingerprint Dive into the research topics of 'Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44'. Together they form a unique fingerprint.

  • Cite this

    Fraldi, A., Zito, E., Annunziata, F., Lombardi, A., Cozzolino, M., Monti, M., Spampanato, C., Ballabio, A., Pucci, P., Sitia, R., & Cosma, M. P. (2008). Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44. Human Molecular Genetics, 17(17), 2610-2621. https://doi.org/10.1093/hmg/ddn161