Chauss Daniel, Brennan Lisa A, Bakina Olga, Kantorow Marc
From the Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida 33431.
From the Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, Florida 33431
J Biol Chem. 2015 Dec 18;290(51):30253-66. doi: 10.1074/jbc.M115.688390. Epub 2015 Nov 2.
Accumulation of apoptotic material is toxic and associated with cataract and other disease states. Identification of mechanisms that prevent accumulation of apoptotic debris is important for establishing the etiology of these diseases. The ocular lens is routinely assaulted by UV light that causes lens cell apoptosis and is associated with cataract formation. To date, no molecular mechanism for removal of toxic apoptotic debris has been identified in the lens. Vesicular debris within lens cells exposed to UV light has been observed raising speculation that lens cells themselves could act as phagocytes to remove toxic apoptotic debris. However, phagocytosis has not been confirmed as a function of the intact eye lens, and no mechanism for lens phagocytosis has been established. Here, we demonstrate that the eye lens is capable of phagocytizing extracellular lens cell debris. Using high throughput RNA sequencing and bioinformatics analysis, we establish that lens epithelial cells express members of the integrin αVβ5-mediated phagocytosis pathway and that internalized cell debris co-localizes with αVβ5 and with RAB7 and Rab-interacting lysosomal protein that are required for phagosome maturation and fusion with lysosomes. We demonstrate that the αVβ5 receptor is required for lens epithelial cell phagocytosis and that UV light treatment of lens epithelial cells results in damage to the αVβ5 receptor with concomitant loss of phagocytosis. These data suggest that loss of αVβ5-mediated phagocytosis by the eye lens could result in accumulation of toxic cell debris that could contribute to UV light-induced cataract formation.
凋亡物质的积累具有毒性，并与白内障及其他疾病状态相关。确定防止凋亡碎片积累的机制对于明确这些疾病的病因至关重要。眼晶状体经常受到紫外线的侵袭，紫外线会导致晶状体细胞凋亡并与白内障形成相关。迄今为止，尚未在晶状体中确定清除有毒凋亡碎片的分子机制。在暴露于紫外线的晶状体细胞内观察到了囊泡碎片，这引发了一种推测，即晶状体细胞本身可能充当吞噬细胞来清除有毒的凋亡碎片。然而，吞噬作用尚未被确认为完整眼晶状体的一项功能，并且尚未建立晶状体吞噬作用的机制。在此，我们证明眼晶状体能够吞噬细胞外的晶状体细胞碎片。通过高通量RNA测序和生物信息学分析，我们确定晶状体上皮细胞表达整合素αVβ5介导的吞噬途径的成员，并且内化的细胞碎片与αVβ5以及与吞噬体成熟和与溶酶体融合所需的RAB7和Rab相互作用溶酶体蛋白共定位。我们证明αVβ5受体是晶状体上皮细胞吞噬作用所必需的，并且紫外线处理晶状体上皮细胞会导致αVβ5受体受损，同时吞噬作用丧失。这些数据表明，眼晶状体αVβ5介导的吞噬作用丧失可能导致有毒细胞碎片的积累，这可能促成紫外线诱导的白内障形成。
