CNRS, Immunologie et Chimie Thérapeutiques, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France.
Autophagy. 2011 May;7(5):539-40. doi: 10.4161/auto.7.5.14845. Epub 2011 May 1.
The P140 phosphopeptide encompassing residues 131-151 of the spliceosomal U1-70K snRNP protein displays protective properties in lupus patients and MRL/lpr mice. It increases peripheral blood lymphocyte apoptosis via a mechanism involving γδ T cells. After intravenous administration, P140 accumulates in the lungs and spleen. It binds both the HSC70/Hsp73 chaperone and MHC class II (MHCII) molecules, which colocalize in splenic MRL/lpr B cells. Expression of HSC70 and MHCII, which is increased in MRL/lpr splenic B cells, is diminished after P140 administration. P140 impairs refolding properties of HSC70 and alters expression of stable MHCII molecules in B lymphocytes. In MRL/lpr B cells, P140 increases the accumulation of the autophagy markers p62/SQSTM1 and LC3-II, consistent with a downregulation of autophagic flux. Our study reveals a very unique property of P140 peptide that alters the autophagy pathway leading to a defect of endogenous (auto)antigen processing in MRL/lpr antigen-presenting B cells and a decrease of T cell priming and signaling.
涵盖剪接体 U1-70K snRNP 蛋白 131-151 位氨基酸残基的 P140 磷酸肽在狼疮患者和 MRL/lpr 小鼠中具有保护作用。它通过涉及 γδ T 细胞的机制增加外周血淋巴细胞凋亡。静脉给药后，P140 积聚在肺和脾脏中。它与 HSC70/Hsp73 伴侣分子和 MHC II 类（MHCII）分子结合，后者在脾 MRL/lpr B 细胞中共定位。MRL/lpr 脾 B 细胞中表达增加的 HSC70 和 MHCII 的表达在 P140 给药后减少。P140 损害 HSC70 的重折叠特性，并改变 B 淋巴细胞中稳定 MHCII 分子的表达。在 MRL/lpr B 细胞中，P140 增加自噬标记物 p62/SQSTM1 和 LC3-II 的积累，与自噬流的下调一致。我们的研究揭示了 P140 肽的一个非常独特的特性，它改变了自噬途径，导致 MRL/lpr 抗原呈递 B 细胞中内源性（自身）抗原加工缺陷，并减少 T 细胞启动和信号转导。
