Mauve/LYST limits fusion of lysosome-related organelles and promotes centrosomal recruitment of microtubule nucleating proteins.

Ramona Lattao,David M Glover,Hélène Rangone,Salud Llamazares

doi:10.1016/j.devcel.2021.02.019

Abstract

SummaryLysosome-related organelles (LROs) are endosomal compartments carrying tissue-specific proteins, which become enlarged in Chediak-Higashi syndrome (CHS) due to mutations in LYST. Here, we show that Drosophila Mauve, a counterpart of LYST, suppresses vesicle fusion events with lipid droplets (LDs) during the formation of yolk granules (YGs), the LROs of the syncytial embryo, and opposes Rab5, which promotes fusion. Mauve localizes on YGs and at spindle poles, and it co-immunoprecipitates with the LDs’ component and microtubule-associated protein Minispindles/Ch-TOG. Minispindles levels are increased at the enlarged YGs and diminished around centrosomes in mauve-derived mutant embryos. This leads to decreased microtubule nucleation from centrosomes, a defect that can be rescued by dominant-negative Rab5. Together, this reveals an unanticipated link between endosomal vesicles and centrosomes. These findings establish Mauve/LYST’s role in regulating LRO formation and centrosome behavior, a role that could account for the enlarged LROs and centrosome positioning defects at the immune synapse of CHS patients.

Highlights

Autosomal recessive Chediak-Higashi syndrome (CHS) results from a mutation in the lysosomal trafficking regulator (LYST) or CHS1 gene and leads to partial albinism, neurological abnormalities, and recurrent bacterial infections (Kaplan et al, 2008; Ward et al, 2000)
Maternal effect mutants of Drosophila mv display enlarged yolk granules (YGs) in the syncytial embryo LYST/CHS1 protein is characterized by pleckstrin homology (PH), BEACH, and WD40 motifs in its C-terminal part, which are conserved in its Drosophila counterpart, Mauve (Figure 1A)
The syncytial embryo’s YGs are prominent, maternally provided lysosome-related organelles (LROs) required for embryonic development suggesting there should be maternal effect lethal (MEL) alleles of mv, i.e., mv mutant mothers whose embryos would not develop

Summary

Introduction

Autosomal recessive Chediak-Higashi syndrome (CHS) results from a mutation in the lysosomal trafficking regulator (LYST) or CHS1 gene and leads to partial albinism, neurological abnormalities, and recurrent bacterial infections (Kaplan et al, 2008; Ward et al, 2000). Despite the formation of a mature IS in CHS NK cells, centrosomes do not correctly polarize and the enlarged LROs neither converge at the centrosome nor translocate to the synapse (Chiang et al, 2017; Gil-Krzewska et al, 2016, 2018) Such findings could reflect defective microtubule (MT) organization by the centrosomes in CHS cells, and while some groups describe CHS centrosomes to nucleate fewer MTs (Boxer et al, 1979; Oliver and Zurier, 1976), others report normal MT numbers, lengths, and distributions (Frankel et al, 1978; Ostlund et al, 1980; Pryzwansky et al, 1985). The consequence of mutation in LYST for centrosome and MT function is unclear

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