Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins.
Cytosolic aggregates perturb the degradation of nontranslocated secretory and membrane proteins.
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DOI：
10.1091/mbc.e10-07-0638
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发表时间：
2011-05-15
影响因子：
3.3
通讯作者：
Hegde RS
中科院分区：
文献类型：
--
作者：
Chakrabarti O;Rane NS;Hegde RS
蛋白质聚集体是许多疾病的共同特征，并且可能具有仍然知之甚少的各种有害作用。在这里，作者表明，胞质聚集体的一个后果是选择性地延迟错误定位的分泌和膜蛋白的降解，导致它们随时间的异常积累。许多疾病都与胞质蛋白聚集体的积累有关。这些聚集体对正常细胞蛋白质稳态的各个方面的影响仍有待确定。在这里，我们发现，胞质聚集，不一定破坏蛋白酶体功能，可以显着延迟非易位分泌和膜蛋白前体的正常快速降解。在哺乳动物朊病毒蛋白（PrP）的情况下，非易位部分被招募到预先存在的聚集体之前，其分类降解。这种招聘允许细胞溶质PrP聚集体的生长和持久性，解释了它们在瞬时蛋白酶体抑制的早期研究中观察到的明显的“自我转换”。对于其他蛋白质，聚集体介导的前体降解延迟导致聚集和/或可溶性驻留在胞质溶胶中，通常导致异常的细胞形态。值得注意的是，提高信号序列效率减轻了聚集体的这些影响。这些观察结果确定了一个以前未被认识到的后果，非易位分泌和膜蛋白，一个轻微的，但潜在的破坏性人口的快速处置，这是至关重要的维持细胞内稳态的胞质聚集体。
Protein aggregates are a common feature of numerous diseases and may have various detrimental effects that remain poorly understood. Here the authors show that one consequence of cytosolic aggregates is to selectively delay degradation of mislocalized secretory and membrane proteins, leading to their aberrant accumulation over time. A wide range of diseases are associated with the accumulation of cytosolic protein aggregates. The effects of these aggregates on various aspects of normal cellular protein homeostasis remain to be determined. Here we find that cytosolic aggregates, without necessarily disrupting proteasome function, can markedly delay the normally rapid degradation of nontranslocated secretory and membrane protein precursors. In the case of mammalian prion protein (PrP), the nontranslocated fraction is recruited into preexisting aggregates before its triage for degradation. This recruitment permits the growth and persistence of cytosolic PrP aggregates, explaining their apparent “self-conversion” seen in earlier studies of transient proteasome inhibition. For other proteins, the aggregate-mediated delay in precursor degradation led to aggregation and/or soluble residence in the cytosol, often causing aberrant cellular morphology. Remarkably, improving signal sequence efficiency mitigated these effects of aggregates. These observations identify a previously unappreciated consequence of cytosolic aggregates for nontranslocated secretory and membrane proteins, a minor but potentially disruptive population the rapid disposal of which is critical to maintaining cellular homeostasis.