Genetic modifiers of abnormal organelle biogenesis in a Drosophila model of BLOC-1 deficiency

被引：52

作者：

Cheli, Veronica T. ^{[1
]}

Daniels, Richard W. ^{[4
]}

Godoy, Ruth ^{[5
]}

Hoyle, Diego J. ^{[1
]}

Kandachar, Vasundhara ^{[6
]}

Starcevic, Marta ^{[1
]}

Martinez-Agosto, Julian A. ^{[1
,2
]}

Poole, Stephen ^{[7
]}

DiAntonio, Aaron ^{[4
]}

Lloyd, Vett K. ^{[5
]}

Chang, Henry C. ^{[6
]}

Krantz, David E. ^{[3
]}

Dell'Angelica, Esteban C. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90095 USA

[4] Washington Univ, Dept Dev Biol, St Louis, MO 63110 USA

[5] Mt Allison Univ, Dept Biol, Sackville, NB E4L 1G7, Canada

[6] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA

[7] Univ Calif Santa Barbara, Dept Mol Cellular & Dev Biol, Santa Barbara, CA 93106 USA

来源：

HUMAN MOLECULAR GENETICS | 2010年 / 19卷 / 05期

基金：

美国国家卫生研究院; 加拿大自然科学与工程研究理事会;

关键词：

HERMANSKY-PUDLAK-SYNDROME; SUSCEPTIBILITY GENE; PIGMENTATION GENE; AP-3; COMPLEX; MOUSE MODEL; WHITE GENE; PROTEIN; SCHIZOPHRENIA; DYSBINDIN; ENCODES;

D O I：

10.1093/hmg/ddp555

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Biogenesis of lysosome-related organelles complex 1 (BLOC-1) is a protein complex formed by the products of eight distinct genes. Loss-of-function mutations in two of these genes, DTNBP1 and BLOC1S3, cause Hermansky-Pudlak syndrome, a human disorder characterized by defective biogenesis of lysosome-related organelles. In addition, haplotype variants within the same two genes have been postulated to increase the risk of developing schizophrenia. However, the molecular function of BLOC-1 remains unknown. Here, we have generated a fly model of BLOC-1 deficiency. Mutant flies lacking the conserved Blos1 subunit displayed eye pigmentation defects due to abnormal pigment granules, which are lysosome-related organelles, as well as abnormal glutamatergic transmission and behavior. Epistatic analyses revealed that BLOC-1 function in pigment granule biogenesis requires the activities of BLOC-2 and a putative Rab guanine-nucleotide-exchange factor named Claret. The eye pigmentation phenotype was modified by misexpression of proteins involved in intracellular protein trafficking; in particular, the phenotype was partially ameliorated by Rab11 and strongly enhanced by the clathrin-disassembly factor, Auxilin. These observations validate Drosophila melanogaster as a powerful model for the study of BLOC-1 function and its interactions with modifier genes.

引用

页码：861 / 878

页数：18

共 96 条

[71]

ROBERTSON HM, 1988, GENETICS, V118, P461

[72] A data-mining approach to rank candidate protein-binding partners-The case of biogenesis of lysosome-related organelles complex-1 (BLOC-1) [J].

Rodriguez-Fernandez, I. A. ;

Dell'Angelica, E. C. .

JOURNAL OF INHERITED METABOLIC DISEASE, 2009, 32 (02) :190-203

[73] Schizophrenia: The "BLOC" May Be in the Endosomes [J].

Ryder, Pearl V. ;

Faundez, Victor .

SCIENCE SIGNALING, 2009, 2 (93) :pe66

[74] ESCRTs and human disease [J].

Saksena, Suraj ;

Emr, Scott D. .

BIOCHEMICAL SOCIETY TRANSACTIONS, 2009, 37 :167-172

[75] BLOC-1 complex deficiency alters the targeting of adaptor protein complex-3 cargoes [J].

Salazar, G. ;

Craige, B. ;

Styers, M. L. ;

Newell-Litwa, K. A. ;

Doucette, M. M. ;

Wainer, B. H. ;

Falcon-Perez, J. M. ;

Dell'Angelica, E. C. ;

Peden, A. A. ;

Werner, E. ;

Faundez, V. .

MOLECULAR BIOLOGY OF THE CELL, 2006, 17 (09) :4014-4026

[76] Hermansky-Pudlak Syndrome Protein Complexes Associate with Phosphatidylinositol 4-Kinase Type II α in Neuronal and Non-neuronal Cells [J].

Salazar, Gloria ;

Zlatic, Stephanie ;

Craige, Branch ;

Peden, Andrew A. ;

Pohl, Jan ;

Faundez, Victor .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (03) :1790-1802

[77] Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis [J].

Sang, TK ;

Li, CJ ;

Liu, WC ;

Rodriguez, A ;

Abrams, JM ;

Zipursky, SL ;

Jackson, GR .

HUMAN MOLECULAR GENETICS, 2005, 14 (03) :357-372

[78] Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly [J].

Sawamura, N. ;

Ando, T. ;

Maruyama, Y. ;

Fujimuro, M. ;

Mochizuki, H. ;

Honjo, K. ;

Shimoda, M. ;

Toda, H. ;

Sawamura-Yamamoto, T. ;

Makuch, L. A. ;

Hayashi, A. ;

Ishizuka, K. ;

Cascella, N. G. ;

Kamiya, A. ;

Ishida, N. ;

Tomoda, T. ;

Hai, T. ;

Furukubo-Tokunaga, K. ;

Sawa, A. .

MOLECULAR PSYCHIATRY, 2008, 13 (12) :1138-1148

[79]

Schwartz AS, 2009, NAT METHODS, V6, P55, DOI [10.1038/NMETH.1283, 10.1038/nmeth.1283]

[80] Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes [J].

Setty, Subba Rao Gangi ;

Tenza, Daniele ;

Sviderskaya, Elena V. ;

Bennett, Dorothy C. ;

Raposo, Graca ;

Marks, Michael S. .

NATURE, 2008, 454 (7208) :1142-U75

← 1 2 3 4 5 6 7 8 9 10 →