Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44
Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44
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DOI：
10.1074/jbc.m115.663088
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发表时间：
2015-07-17
影响因子：
4.8
通讯作者：
Mitra, Alok K.
中科院分区：
文献类型：
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作者：
Hampe, Lutz;Radjainia, Mazdak;Mitra, Alok K.
脂联素是一种由脂肪细胞大量分泌的胶原性激素，具有很强的抗糖尿病和抗炎作用。通过位于N末端可变区的保守Cys（39）介导，三聚体（低分子量（LMW））脂联素亚基组装成不同的高级复合物，例如六聚体（中分子量（MMW））和12-18-聚体（高分子量（HMW）），后者主要负责脂联素的胰岛素增敏活性。内质网（ER）伴侣ERp 44将脂联素保留在早期分泌室中，并严格控制Cys 39的氧化状态和脂联素的寡聚化。使用细胞和体外试验，我们表明，ERp 44特异性识别LMW和MMW形式，但不高分子量形式。我们用脂联素的短肽模拟物进行的结合试验表明，ERp 44拦截并转化完全氧化的LMW和MMW脂联素，而不是HMW形式，转化为还原的三聚体前体。这些在顺式高尔基体中的ERp 44结合前体可以转运回ER并释放，以增强具有适当氧化状态的脂联素中间体的群体，从而支持ERp 44质量控制的过程。
Adiponectin, a collagenous hormone secreted abundantly from adipocytes, possesses potent antidiabetic and anti-inflammatory properties. Mediated by the conserved Cys(39) located in the variable region of the N terminus, the trimeric (low molecular weight (LMW)) adiponectin subunit assembles into different higher order complexes, e.g. hexamers (middle molecular weight (MMW)) and 12-18-mers (high molecular weight (HMW)), the latter being mostly responsible for the insulin-sensitizing activity of adiponectin. The endoplasmic reticulum (ER) chaperone ERp44 retains adiponectin in the early secretory compartment and tightly controls the oxidative state of Cys39 and the oligomerization of adiponectin. Using cellular and in vitro assays, we show that ERp44 specifically recognizes the LMW and MMW forms but not the HMW form. Our binding assays with short peptide mimetics of adiponectin suggest that ERp44 intercepts and converts the pool of fully oxidized LMW and MMW adiponectin, but not the HMW form, into reduced trimeric precursors. These ERp44-bound precursors in the cis-Golgi may be transported back to the ER and released to enhance the population of adiponectin intermediates with appropriate oxidative state for HMW assembly, thereby underpinning the process of ERp44 quality control.