暗蛋白质组(dark proteome)指难以通过实验解析或同源建模预测三维结构的蛋白质或序列区域, 常来源于非经典开放阅读框,包括lncRNA、mRNA 非翻译区、circRNA 及可变剪接产生的隐匿编码序列。随着蛋白质组学的进展,暗蛋白在免疫系统中的重要功能逐渐被揭示。其普遍结构短小、缺乏已知结构域,但可能具备稳定折叠, 使其能够调控信号通路、蛋白质加工及组织特异性功能。在免疫过程中, 暗蛋白参与抗原呈递、肿瘤免疫、炎症反应调控及病毒免疫逃逸,成为免疫相关疾病研究的新热点。例如, 非经典开放阅读框来源的微蛋白可作为MHC-I呈递的重要抗原来源; 病毒暗蛋白利用内在无序结构干扰宿主抗病毒途径;部分微蛋白则在自身免疫与炎症性疾病中发挥调节作用。随着其在癌症、神经退行性疾病及感染性疾病中的关键作用不断被发现,暗蛋白正成为潜在的生物标志物与治疗靶点, 为精准医学和药物研发带来新的机遇。
吾克来·吐尔得别克1
,
2
,
3
,
冯金妍1
,
2
,
3
,
张俊佳1
,
2
,
3
,
沈世雄1
,
2
,
3
,
4
,
初 明1
,
2
,
3
,
张 鑫5
,
李 民4
,
△
,
王月丹1
,
2
,
3
,
△
. 暗蛋白质组:免疫相关疾病的潜在治疗新靶点与生物标志物[J]. 生理科学进展, 2026
, 57(3)
: 289
-298
.
DOI: 10.20059/j.cnki.pps.2026.02.1340
The dark proteome refers to proteins or sequence regions whose three-dimensional structures cannot be resolved experimentally or reliably predicted by homology modeling. These elements often originate from noncanonical open reading frames, including those embedded in lncRNAs, the untranslated regions of mRNAs, circular RNAs, and cryptic coding sequences generated by alternative splicing. With advances in proteomics, the critical roles of dark proteins in the immune system have increasingly come to light. Typically short, lacking known structural domains yet potentially possessing stable folding characteristics, dark proteins participate in signaling regulation, protein processing, and tissue-specific biological functions. Within immune processes, they are involved in antigen presentation, tumor immunity,inflammatory regulation, and viral immune evasion, making them an emerging focus in immune-related disease research. For example, microproteins derived from ncORFs can serve as important sources of MHC-I-presented antigens; viral dark proteins exploit intrinsically disordered regions to disrupt host antiviral pathways; and some microproteins modulate autoimmune and inflammatory responses. As their essential roles in cancer, neurodegenerative disorders, and infectious diseases continue to be uncovered, the dark proteome is increasingly recognized as a promising reservoir of novel biomarkers and therapeutic targets, offering new opportunities for precision medicine and drug development.
