Center for Stem Cell and Regenerative Disease, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM), the University of Texas-Health Science Center at Houston, Houston, Texas, USA.
Autophagy. 2022 Apr;18(4):783-798. doi: 10.1080/15548627.2021.1956105. Epub 2021 Aug 12.
Until recently, the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy were considered to be two independent systems that target proteins for degradation by proteasomes or via lysosomes, respectively. Here, we report that TRIM44 (tripartite motif containing 44) is a novel link that connects the UPS system with the autophagy degradation pathway. Suppressing the UPS degradation pathway leads to TRIM44 upregulation, which further promotes aggregated protein clearance through the binding of K48 ubiquitin chains on proteins. TRIM44 expression activates autophagy via promoting SQSTM1/p62 oligomerization, which rapidly increases the rate of aggregate protein removal. Overall, our data reveal that TRIM44 is a newly identified link between the UPS system and the autophagy pathway. Delineating the cross-talk between these two degradation pathways may reveal new mechanisms of targeting aggregate-prone diseases, such as cancer and neurodegenerative disease.: 3-MA: 3-methyladenine; ACTB: actin beta; ATG5: autophagy related 5; BB: B-box domain; BECN1: beclin1; BM: bone marrow; CC: coiled-coil domain; CFTR: cystic fibrosis transmembrane conductance regulator; CON: control; CQ: chloroquine; DOX: doxycycline; DSP: dithiobis(succinimidly propionate); ER: endoplasmic reticulum; FI: fluorescence intensity; FL: full length; HIF1A/HIF-1#x3B1;: hypoxia inducible factor 1 subunit alpha; HSC: hematopoietic stem cells; HTT: huntingtin; KD: knockdown; KD-CON: knockdown construct control; MM: multiple myeloma; MTOR: mechanistic target of rapamycin kinase; NP-40: nonidet P-40; NFE2L2/NRF2: nuclear factor, erythroid 2 like 2; OE: overexpression; OE-CON: overexpression construct control; PARP: poly (ADP-ribose) polymerase; SDS: sodium dodecyl sulfate; SQSTM1/p62: sequestosome 1; Tet-on: tetracycline; TRIM44: tripartite motif containing 44; UPS: ubiquitin-proteasome system; ZF: zinc-finger.
直到最近，泛素蛋白酶体系统（UPS）和巨自噬/自噬被认为是两个独立的系统，分别通过蛋白酶体或溶酶体靶向蛋白质降解。在这里，我们报告 TRIM44（包含三部分基序的 44 号）是连接 UPS 系统与自噬降解途径的新链接。抑制 UPS 降解途径会导致 TRIM44 上调，这进一步通过蛋白质上的 K48 泛素链结合促进聚集蛋白的清除。TRIM44 表达通过促进 SQSTM1/p62 寡聚化来激活自噬，从而迅速提高聚集体蛋白的去除率。总的来说，我们的数据表明 TRIM44 是 UPS 系统和自噬途径之间新发现的联系。阐明这两种降解途径之间的串扰可能会揭示针对易聚集疾病（如癌症和神经退行性疾病）的新靶向机制。3-MA：3-甲基腺嘌呤；ACTB：肌动蛋白 B；ATG5：自噬相关 5；BB：B 盒结构域；BECN1：beclin1；BM：骨髓；CC：卷曲螺旋结构域；CFTR：囊性纤维化跨膜电导调节剂；CON：对照；CQ：氯喹；DOX：多西环素；DSP：二硫代双琥珀酰亚胺丙酸酯；ER：内质网；FI：荧光强度；FL：全长；HIF1A/HIF-1#x3B1：缺氧诱导因子 1 亚基 alpha；HSC：造血干细胞；HTT：亨廷顿蛋白；KD：敲低；KD-CON：敲低对照构建体；MM：多发性骨髓瘤；MTOR：雷帕霉素靶蛋白激酶；NP-40：非离子型去垢剂 40；NFE2L2/NRF2：核因子，红细胞 2 样 2；OE：过表达；OE-CON：过表达对照构建体；PARP：多聚（ADP-核糖）聚合酶；SDS：十二烷基硫酸钠；SQSTM1/p62：自噬体相关蛋白 1；Tet-on：四环素；TRIM44：包含三部分基序的 44 号；UPS：泛素蛋白酶体系统；ZF：锌指。
