CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover
CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover
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DOI：
10.1182/blood-2006-05-023556
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发表时间：
2007-02-01
期刊：
影响因子：
20.3
通讯作者：
Johnston, James A.
中科院分区：
文献类型：
--
作者：
Orr, Selinda J.;Morgan, Nuala M.;Johnston, James A.
CD33是唾液酸结合免疫球蛋白样凝集素(Siglec)抑制受体家族的成员，是急性髓系白血病(AML)的治疗靶点。CD33含有胞质免疫受体酪氨酸抑制基序(ITIM)，可募集SHP-1和SHP-2。CD33的表达是如何调控的还不清楚。细胞因子信号转导抑制因子3(SOCS3)受细胞因子、LIPs和其他PAMP的影响而表达，并与SHP-1/2竞争结合到细胞因子受体的ITIMs上，从而抑制信号转导。在本研究中，通过肽下拉实验，我们发现SOCS3可以与CD33的磷酸化ITIM特异性结合。此外，在交联化之后，SOCS3可以招募ECS E3连接酶，从而加速CD33和SOCS3的蛋白酶体降解。我们的数据表明，CD33中的酪氨酸基序对于内化并不重要，而它们是降解所必需的。此外，SOCS3还能抑制CD33诱导的细胞因子诱导的增殖。这是第一个被SOCS3降解的受体，SOCS3和它的目标蛋白同时被降解。我们的发现清楚地表明，在炎症反应中，抑制性受体CD33通过这一机制丢失。此外，这具有重要的临床意义，因为表达SOCS3的肿瘤可能对α-CD33治疗无效。
CD33 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic Immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LIPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to alpha-CD33 therapy.