A potentially dynamic lysosomal role for the endogenous TRPML proteins

Journal of Pathology - Tập 219 Số 2 - Trang 153-162 - 2009
David A. Zeevi1, Ayala Frumkin1, Vered Offen‐Glasner1, Aviram Kogot‐Levin1, Gideon Bach2
1Department of Human Genetics, Hadassah-Hebrew University Hospital, Jerusalem, Israel.
2Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, Israel

Tóm tắt

AbstractLysosomal storage disorders (LSDs) constitute a diverse group of inherited diseases that result from lysosomal storage of compounds occurring in direct consequence to deficiencies of proteins implicated in proper lysosomal function. Pathology in the LSD mucolipidosis type IV (MLIV), is characterized by lysosomal storage of lipids together with water‐soluble materials in cells from every tissue and organ of affected patients. Mutations in the mucolipin 1 (TRPML1) protein cause MLIV and TRPML1 has also been shown to interact with two of its paralogous proteins, mucolipin 2 (TRPML2) and mucolipin 3 (TRPML3), in heterologous expression systems. Heterogeneous lysosomal storage is readily identified in electron micrographs of MLIV patient cells, suggesting that proper TRPML1 function is essential for the maintenance of lysosomal integrity. In order to investigate whether TRPML2 and TRPML3 also play a role in the maintenance of lysosomal integrity, we conducted gene‐specific knockdown assays against these protein targets. Ultrastructural analysis revealed lysosomal inclusions in both TRPML2 and TRPML3 knockdown cells, suggestive of a common mechanism for these proteins, in parallel with TRPML1, in the regulation of lysosomal integrity. However, co‐immunoprecipitation assays revealed that physical interactions between each of the endogenous TRPML proteins are quite limited. In addition, we found that all three endogenous proteins only partially co‐localize with each other in lysosomal as well as extra‐lysosomal compartments. This suggests that native TRPML2 and TRPML3 might participate with native TRPML1 in a dynamic form of lysosomal regulation. Given that depletion of TRPML2/3 led to lysosomal storage typical to an LSD, we propose that depletion of these proteins might also underlie novel LSD pathologies not described hitherto. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Từ khóa


Tài liệu tham khảo

ValleD BeaudetAL VogelsteinB KinzlerKW AntonarakisSE BallabioA. The Online Metabolic and Molecular Bases of Inherited Disease.www.ommbid.com/[accessed 28 January 2009].

10.1001/archneur.60.3.322

10.1038/nrm1423

10.1080/01913120500520986

10.1016/j.bbamcr.2008.11.004

10.1091/mbc.E02-01-0031

10.1016/S0092-8674(03)00347-7

10.1016/S0092-8674(03)00348-9

10.1002/humu.20040

10.1038/sj.embor.7400454

10.1006/mgme.2001.3195

10.1002/humu.1115

10.1074/jbc.M600807200

10.1016/j.bbadis.2007.01.004

10.1152/ajprenal.90522.2008

10.1038/nature07311

10.1007/s00424-004-1361-7

10.1016/S0022-3476(74)80671-2

Merin S, 1975, Mucolipidosis IV: ocular, systemic and ultrastructural findings, Invest Ophthal, 14, 437

10.1016/0002-9394(75)90532-2

10.1001/archneur.1976.00500120032005

Goebel HH, 1982, Morphological and chemical biopsy findings in mucolipidosis IV, Clin Neuropathol, 1, 73

10.2174/1566524023362276

10.1084/jem.20072194

10.1212/WNL.59.3.306

10.4161/auto.3906

10.1111/j.1600-0854.2006.00387.x

10.1111/j.1600-0854.2006.00475.x

10.1016/j.febslet.2004.04.080

10.1074/jbc.M511104200

10.1074/jbc.M508210200

10.1111/j.1600-0854.2007.00619.x

10.1074/jbc.C700190200

10.1073/pnas.0709096104

10.1073/pnas.0709846104

10.1203/00006450-199506000-00003

10.1093/emboj/cdg080

10.1085/jgp.200709731

10.1074/jbc.M306705200

10.1046/j.1432-1033.2001.02500.x

10.1073/pnas.102596199

10.1074/jbc.M103272200

10.1016/S0143-4160(03)00061-7

10.1074/jbc.M403321200

10.1038/sj.emboj.7601792

10.1038/ng0501-64

10.1073/pnas.062065399

10.1086/521954

10.1016/j.cell.2008.09.041

10.1073/pnas.0400709101

10.1074/jbc.M607982200

10.1016/j.ceca.2007.12.005

10.1093/hmg/ddn174

10.1002/jcp.21676

10.1093/hmg/ddm289

10.1038/79095

10.1093/hmg/9.17.2471

10.1016/S0002-9297(07)62941-3

10.1073/pnas.222425399

10.1073/pnas.0707963105

10.1113/jphysiol.2008.156992

Thông tin
Thông tin xuất bản

Journal of Pathology

Tập 219 Số 2

153-162

Thông tin tác giả