Novel Role of TRPML2 in the Regulation of the Innate Immune Response

被引:74
作者
Sun, Lu [1 ]
Hua, Yinan [1 ]
Vergarajauregui, Silvia [1 ]
Diab, Heba I. [1 ]
Puertollano, Rosa [1 ]
机构
[1] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA
基金
美国国家卫生研究院;
关键词
MUCOLIPIDOSIS TYPE-IV; LYSOSOMAL BIOGENESIS; TRANSCRIPTION FACTOR; ENDOSOMAL PATHWAY; PROTEIN TRPML1; TRAFFICKING; CHANNEL; GENE; AUTOPHAGY; CELLS;
D O I
10.4049/jimmunol.1500163
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
TRPMLs (or mucolipins) constitute a family of endosomal cation channels with homology to the transient receptor potential superfamily. In mammals, the TRPML family includes three members: TRPML1-3. Although TRPML1 and TRPML3 have been well characterized, the cellular function of TRPML2 has remained elusive. To address TRPML2 function in a physiologically relevant cell type, we first analyzed TRPML2 expression in different mouse tissues and organs and found that it was predominantly expressed in lymphoid organs and kidney. Quantitative RT-PCR revealed tight regulation of TRPML2 at the transcriptional level. Although TRPML2 expression was negligible in resting macrophages, TRPML2 mRNA and protein levels dramatically increased in response to TLR activation both in vitro and in vivo. Conversely, TRPML1 and TRPML3 levels did not change upon TLR activation. Immunofluorescence analysis demonstrated that endogenous TRPML2 primarily localized to recycling endosomes both in culture and primary cells, in contrast with TRPML1 and TRPML3, which distribute to the late and early endosomal pathway, respectively. To better understand the in vivo function of TRPML2, we generated a TRPML2-knockout mouse. We found that the production of several chemokines, in particular CCL2, was severely reduced in TRPML2-knockout mice. Furthermore, TRPML2-knockout mice displayed impaired recruitment of peripheral macrophages in response to i.p. injections of LPS or live bacteria, suggesting a potential defect in the immune response. Overall, our study reveals interesting differences in the regulation and distribution of the members of the TRPML family and identifies a novel role for TRPML2 in the innate immune response.
引用
收藏
页码:4922 / 4932
页数:11
相关论文
共 40 条
[1]   Role of TRP Channels in the Regulation of the Endosomal Pathway [J].
Abe, Ken ;
Puertollano, Rosa .
PHYSIOLOGY, 2011, 26 (01) :14-22
[2]   The neurogenetics of mucolipidosis type IV [J].
Altarescu, G ;
Sun, M ;
Moore, DF ;
Smith, JA ;
Wiggs, EA ;
Solomon, BI ;
Patronas, NJ ;
Frei, KP ;
Gupta, S ;
Kaneski, CR ;
Quarrell, OW ;
Slaugenhaupt, SA ;
Goldin, E ;
Schiffmann, R .
NEUROLOGY, 2002, 59 (03) :306-313
[3]  
AMIR N, 1987, PEDIATRICS, V79, P953
[4]   Identification of the gene causing mucolipidosis type IV [J].
Bargal, R ;
Avidan, N ;
Ben-Asher, E ;
Olender, Z ;
Zeigler, M ;
Frumkin, A ;
Raas-Rothschild, A ;
Glusman, G ;
Lancet, D ;
Bach, G .
NATURE GENETICS, 2000, 26 (01) :118-121
[5]   Cloning of the gene encoding a novel integral membrane protein, mucolipidin - and identification of the two major founder mutations causing mucolipidosis type IV [J].
Bassi, MT ;
Manzoni, M ;
Monti, E ;
Pizzo, MT ;
Ballabio, A ;
Borsani, G .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (05) :1110-1120
[6]   CONGENITAL CORNEAL CLOUDING WITH ABNORMAL SYSTEMIC STORAGE BODIES - NEW VARIANT OF MUCOLIPIDOSIS [J].
BERMAN, ER ;
LIVNI, N ;
SHAPIRA, E ;
MERIN, S ;
LEVIJ, IS .
JOURNAL OF PEDIATRICS, 1974, 84 (04) :519-526
[7]   Inferences, questions and possibilities in toll-like receptor signalling [J].
Beutler, B .
NATURE, 2004, 430 (6996) :257-263
[8]   Role of chemokine CCL2 and its receptor CCR2 in neurodegenerative diseases [J].
Bose, Shambhunath ;
Cho, Jungsook .
ARCHIVES OF PHARMACAL RESEARCH, 2013, 36 (09) :1039-1050
[9]   Expression and Vesicular Localization of Mouse Trpml3 in Stria Vascularis, Hair Cells, and Vomeronasal and Olfactory Receptor Neurons [J].
Castiglioni, Andrew J. ;
Remis, Natalie N. ;
Flores, Emma N. ;
Garcia-Anoveros, Jaime .
JOURNAL OF COMPARATIVE NEUROLOGY, 2011, 519 (06) :1095-1114
[10]   Mutations in Mcoln3 associated with deafness and pigmentation defects in varitint-waddler (Va) mice [J].
Di Palma, F ;
Belyantseva, IA ;
Kim, HJ ;
Vogt, TF ;
Kachar, B ;
Noben-Trauth, K .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (23) :14994-14999