ERp44は小胞体のタンパク | 阿波の梟のブログ
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ERp44は小胞体のタンパク

  • ERp44は小胞体のタンパク質であり、オリゴマー形成や分泌の制御、分泌タンパク質の品質管理に関与している。
  • ERp44ノックアウトマウスは低血圧を示し、血液中のアンジオテンシンIIの分解が速いことが示唆される。
  • ERAP1はERp44とジスルフィド結合を形成し、小胞体内に留まることができる。ERp44が欠損するとERAP1が細胞外に分泌され、血圧低下を引き起こす可能性がある。
  • 敗血症モデルでは、ERp44とERAP1の結合が増加し、血圧低下が抑制される。
  • ERp44の酸化還元状態がERAP1の細胞内外の局在を制御し、血圧を調節する可能性がある。
  • ERp44とERAP1の相互作用が、血圧の変動に影響を与えることが示唆され、小胞体の酸化還元状態が関連する疾患の理解に役立つ可能性がある。
  • 小胞体には多くの分子シャペロンやタンパク質修飾酵素が存在し、ERp44はその中の一つであり、分泌タンパク質や膜タンパク質の正常な立体構造やオリゴマーの形成を制御している。
  • ERp44ノックアウトマウスは低血圧を示すことが明らかになり、血液中のアンジオテンシンIIの分解速度が速いことが関連している。
  • ERAP1はERp44とジスルフィド結合を形成し、小胞体内にとどまることができる。ERp44が欠損するとERAP1が細胞外に分泌され、血圧低下を引き起こす可能性がある。
  • 敗血症モデルでは、ERp44とERAP1の結合が増加し、血圧低下が抑制される。
  • ERp44の酸化還元状態がERAP1の細胞内外の局在を制御し、血圧を調節する可能性がある。
  • ERp44とERAP1の相互作用が、血圧の変動に影響を与えることが示唆され、小胞体の酸化還元状態が関連する疾患の理解に役立つ可能性がある。
  • The endoplasmic reticulum protein ERp44 controls the oligomer formation and secretion of various proteins, playing a role in quality control of secretory proteins. However, the physiological function of ERp44 at the individual level in mice has been largely unclear. In this study, the authors generated ERp44 knockout mice and demonstrated that these knockout mice exhibit hypotension. Furthermore, in wild-type mice, the enzyme ERAP1, which degrades angiotensin II, forms disulfide bonds with ERp44 and remains in the endoplasmic reticulum. In ERp44 knockout mice, however, ERAP1 fails to remain in the endoplasmic reticulum and is excessively secreted into the extracellular space. As a result, angiotensin II is degraded in the bloodstream, leading to hypotension. In a sepsis model characterized by rapid blood pressure decrease, an increased binding between ERp44 and ERAP1 was observed, which suppressed the blood pressure decrease. These findings suggest that ERp44 in the endoplasmic reticulum regulates the localization of ERAP1, depending on the redox state, and thereby controls blood pressure.

Introduction:

  • The endoplasmic reticulum (ER) contains numerous molecular chaperones and protein modification enzymes that control the proper folding of secretory and membrane proteins. ERp44 is one such molecular chaperone with a thioredoxin-like domain, and it has been reported to regulate the formation of oligomers in immunoglobulins and adiponectin, as well as the localization of the ER-resident oxidoreductases Ero1 and Prdx4. However, the physiological functions of ERp44 at the individual level in mice have been largely unknown. In this study, the authors generated ERp44 knockout mice and analyzed the roles of ERp44 at the organismal level.
  1. ERp44 knockout mice exhibit hypotension:
  • Initially, ERp44 knockout mice were generated from the C57BL/6 strain. While these knockout mice were born at a rate of 12%, they exhibited overall smaller body size compared to wild-type mice, with nearly all of them dying within 24 hours after birth. However, when ERp44 knockout mice were bred with the FVB/NJ strain, most of them survived to adulthood. Both strains of ERp44 knockout mice showed phenotypic characteristics such as renal tubular dilation and reduced urine output. These phenotypic similarities to angiotensinogen knockout mice prompted the measurement of blood pressure, which revealed a significant decrease in blood pressure compared to wild-type mice. Additionally, the concentration of angiotensin II in the blood was found to be reduced.
  1. Accelerated degradation of angiotensin II in the blood of ERp44 knockout mice:
  • To investigate the reason for the reduced concentration of angiotensin II in the blood of ERp44 knockout mice, the authors examined the synthesis pathway of angiotensin II. There were no abnormalities in the expression levels of angiotensinogen, renin, or angiotensin-converting enzyme, the precursors and enzymes involved in angiotensin II synthesis, respectively. Therefore, the hypothesis of decreased stability of angiotensin II in ERp44 knockout mouse serum was proposed. When synthetic angiotensin II was added to serum from wild-type or ERp44 knockout mice and incubated at 37°C, the serum from ERp44 knockout mice was found to degrade angiotensin II more rapidly than that from wild-type mice. Additionally, the activity of leucine aminopeptidase, an enzyme involved in angiotensin II degradation, was found to be elevated in the blood of ERp44 knockout mice.
  1. ERAP1 forms disulfide bonds with ERp44 and remains in the ER:

  • Previous studies have reported that ERp44 binds to various proteins, regulating their oligomerization and secretion. Therefore, it was hypothesized that an enzyme capable of degrading angiotensin II, which forms disulfide bonds with ERp44, remains in the ER and is excessively secreted into the bloodstream in the absence of ERp44. By analyzing proteins that bind to ERp44 in liver extracts using mass spectrometry, ERAP1, a leucine aminopeptidase enzyme that degrades angiotensin II, was identified as a binding partner of ERp44. The binding between ERp44 and ERAP1 decreased upon treatment with dithiothreitol, suggesting that their interaction depends on the redox state. ERAP1 was initially reported as a secretory protein but was later found to reside in the ER, suggesting a mechanism that retains ERAP1 in the ER. Further analysis revealed that specific amino acid sequences in ERAP1 and ERp44 are crucial for their binding, and disruption of this interaction led to increased secretion of ERAP1 into the extracellular space. Moreover, ERAP1 was predominantly retained intracellularly in wild-type fibroblasts, while it was rapidly secreted within 1 hour in ERp44 knockout fibroblasts.

  • The decreased stability of angiotensin II in the blood of ERp44 knockout mice was confirmed to be mediated by ERAP1. ERAP1 was detected in the blood serum of ERp44 knockout mice but not in that of wild-type mice. Removal of ERAP1 from the serum by anti-ERAP1 antibodies abolished the difference in angiotensin II degradation rates between wild-type and ERp44 knockout mice. Therefore