ESCRT-dependent cell death in a Caenorhabditis elegans model of the lysosomal storage disorder Mucolipidosis type IV

Julie M. Huynh, Hope Dang, Isabel A. Munoz-Tucker, Marvin O’Ketch, Ian T. Liu, Savannah Perno, Natasha Bhuyan, Allison Crain, Ivan Borbon, Hanna F Fares

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Mutations in MCOLN1, which encodes the cation channel protein TRPML1, result in the neurodegenerative lysosomal storage disorder Mucolipidosis type IV. Mucolipidosis type IV patients show lysosomal dysfunction in many tissues and neuronal cell death. The ortholog of TRPML1 in Caenorhabditis elegans is CUP-5; loss of CUP-5 results in lysosomal dysfunction in many tissues and death of developing intestinal cells that results in embryonic lethality. We previously showed that a null mutation in the ATP-Binding Cassette transporter MRP-4 rescues the lysosomal defect and embryonic lethality of cup-5(null) worms. Here we show that reducing levels of the Endosomal Sorting Complex Required for Transport (ESCRT)-associated proteins DID-2, USP-50, and ALX-1/EGO-2, which mediate the final de-ubiquitination step of integral membrane proteins being sequestered into late endosomes, also almost fully suppresses cup-5(null) mutant lysosomal defects and embryonic lethality. Indeed, we show that MRP-4 protein is hypo-ubiquitinated in the absence of CUP-5 and that reducing levels of ESCRT-associated proteins suppresses this hypo-ubiquitination. Thus, increased ESCRT-associated de-ubiquitinating activity mediates the lysosomal defects and corresponding cell death phenotypes in the absence of CUP-5.

Original languageEnglish (US)
Pages (from-to)619-638
Number of pages20
JournalGenetics
Volume202
Issue number2
DOIs
StatePublished - Feb 1 2016

Keywords

  • CUP-5
  • ESCRT
  • Lysosome
  • Mucolipidosis type IV
  • TRPML1

ASJC Scopus subject areas

  • Genetics

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    Huynh, J. M., Dang, H., Munoz-Tucker, I. A., O’Ketch, M., Liu, I. T., Perno, S., Bhuyan, N., Crain, A., Borbon, I., & Fares, H. F. (2016). ESCRT-dependent cell death in a Caenorhabditis elegans model of the lysosomal storage disorder Mucolipidosis type IV. Genetics, 202(2), 619-638. https://doi.org/10.1534/genetics.115.182485