A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.
A nonaggregating surfactant protein C mutant is misdirected to early endosomes and disrupts phospholipid recycling.
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DOI：
10.1111/j.1600-0854.2011.01223.x
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发表时间：
2011-09
期刊：
影响因子：
--
通讯作者：
Mulugeta S
中科院分区：
文献类型：
--
作者：
Beers MF;Hawkins A;Maguire JA;Kotorashvili A;Zhao M;Newitt JL;Ding W;Russo S;Guttentag S;Gonzales L;Mulugeta S
Interstitial lung disease in both children and adults has been linked to mutations in the lung-specific Surfactant protein C gene (SFTPC). Among these, the missense mutation (isoleucine to threonine at codon 73 = hSP-CI73T) accounts for ~30% of all described SFTPC mutations. We reported previously that unlike the BRICHOS misfolding SFTPC mutants, expression of hSP-CI73T induces lung remodeling and alveolar lipoproteinosis without a substantial ER stress response or ER-mediated intrinsic apoptosis. We show here that, in contrast to its wild type counterpart that is directly routed to lysosomal-like organelles for processing, SP-CI73T is misdirected to the plasma membrane and subsequently internalized to the endocytic pathway via early endosomes, leading to the accumulation of abnormally processed proSP-C isoforms. Functionally, cells expressing hSP-CI73T demonstrated both impaired uptake and degradation of surfactant phospholipid, thus providing a molecular mechanism for the observed lipid accumulation in patients expressing hSP-CI73T through the disruption of normal phospholipid recycling. Our data provide evidence for a novel cellular mechanism for conformational protein associated diseases, and suggest a paradigm for mistargeted proteins involved in the disruption of the endosomal/lysosomal sorting machinery.
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DOI：
10.1164/ajrccm.162.2.9910032
发表时间：
2000-08-01
影响因子：
24.7
作者：
Kitamura, T;Uchida, K;Nakata, K
通讯作者：
Nakata, K
DOI：
10.1152/ajplung.00127.2002
发表时间：
2002-11-01
影响因子：
4.9
作者：
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通讯作者：
Ballard, PL
影响因子：
4.8
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Conkright, JJ;Bridges, JP;Weaver, TE
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Weaver, TE
影响因子：
4
作者：
Guillot, L.;Epaud, R.;Feldmann, D.
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DOI：
10.1165/ajrcmb.24.3.4312
发表时间：
2001-03-01
影响因子：
6.4
作者：
Johnson, AL;Braidotti, P;Beers, MF
通讯作者：
Beers, MF