iNOS Aggresome as a Prototype of a Physiologic Aggresome

蛋白质的错误折叠在几种肺部疾病的发病机制中起重要作用。折叠错误和 聚集的蛋白质在细胞中通过伴侣介导的折叠来处理，或者被破坏 蛋白酶体降解。最近的证据表明，细胞已经进化出了第三条途径，包括 错误折叠的蛋白质被隔离到靠近细胞核的专门的“保持站”中，称为侵袭体。 认识到这一主题的重要性，NHLBI召开了一次研讨会，审查与蛋白质加工相关的 问题。研讨会强调有必要了解侵略者的性质和作用 其形成的细胞机制。 我们发现细胞通过侵袭体调节诱导型一氧化氮合酶(INOS) 队形。这个新发现的iNOS侵袭体是第一个被描述的非侵袭体 与蛋白质错误折叠有关，我们称之为“生理攻击性”。这一发现奠定了基础 寻找一个独特的研究机会。对生理攻击性的研究应该揭示丰富的信息 关于细胞如何通过侵袭体的形成来调节蛋白质。 我们假设：a)iNOS生理性侵袭体与以前的 被描述为与错误折叠的蛋白质有关的“病理性”侵袭体。因此，病理性侵袭者可能 仅仅代表了已建立的生理调节过程的加速。B)监管 细胞中侵袭体的形成与细胞及时降解蛋白质的能力有关。无论何时单元格 感觉这一能力很可能由于错误折叠的蛋白质或大的 一定数量的蛋白质，它们会引发侵袭性的形成。细胞采取攻击性手段的决定 形成导致特定的蛋白质迁移参与形成和调节 咄咄逼人。 为了验证这些假设，我们提出了以下具体目标的研究：1)表征 诱导型一氧化氮合酶侵袭体的形成和调控机制2)诱导型一氧化氮合酶形成蛋白的鉴定 咄咄逼人。3)检测错折叠突变蛋白细胞中iNOS侵袭体的调控 与肺部疾病有关，如A1-抗胰蛋白酶突变体。建议进行研究的理由是，一旦 这些机制被理解了，它们将极大地增加我们对细胞处理的理解 错误折叠的蛋白质。未来的治疗策略可以被设计成调节这些细胞反应 疾病状态。

Misfolding of proteins plays an important part in the pathogenesis of several lung diseases. Misfolded and aggregated proteins are handled in the cell through chaperone-mediated refolding, or destroyed by proteasomal degradation. Recent evidence suggests that cells have evolved a third pathway that involves sequestration of misfolded proteins into specialized "holding stations", close to the nucleus, called aggresomes. Recognizing the importance of this topic, the NHLBI convened a workshop to review protein processing related issues. The workshop emphasized the need for understanding the nature and the role of aggresome and the cellular mechanisms of its formation. We have discovered that cells regulate inducible nitric oxide synthase (iNOS) through aggresome formation. This newly discovered iNOS aggresome is the first described occurrence of an aggresome that is not associated with protein misfolding and which we termed "physiologic aggresome". This discovery sets the stage for a unique research opportunity. Study of the physiologic aggresome should reveal a wealth of information regarding how cells regulate proteins through aggresome formation. We hypothesize that: A) iNOS physiologic aggresome shares certain features with what previously described as "pathologic" aggresome associated with misfolded proteins. Thus, pathologic aggresome may merely represent an acceleration of an established physiologic regulatory process. B) The regulation of aggresome formation in cells is linked to cell capacity to degrade proteins in a timely manner. Whenever cells sense that this capacity is likely to be exceeded due to the generation of either a misfolded protein or a large amount of a certain protein, they trigger aggresome formation. The decision of cells to resort to aggresome formation results in specific proteins migrating to participate in the formation and the regulation of the aggresome. To test these hypotheses we propose studies with the following specific aims: 1) Characterization of mechanisms of formation and regulation of iNOS aggresome. 2) Identification of proteins forming iNOS aggresome. 3) Examination of the regulation of iNOS aggresome in cells harboring misfolded mutant proteins related to lung disease such as a1-antitrypsin mutants. The rationale for the proposed studies is that once these mechanisms are understood, they would greatly increase our understanding of cellular handing of misfolded proteins. Future therapeutic strategies can be designed to regulate these cellular responses in disease states.