Gourkanti Saroj, Munoz Yazmin, Cheung Jacqueline, Chavez Rosa M, Agarwal Devanshi, Schoen Taylor J, Solorio-Kirpichyan Kristina, Neal Sonya E
Department of Cell and Developmental Biology, School of Biological Sciences, University of California San Diego, San Diego, California, USA.
Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
J Cell Physiol. 2025 Sep;240(9):e70094. doi: 10.1002/jcp.70094.
The rhomboid superfamily, comprising both proteases and pseudoproteases, has emerged as a central regulator of membrane biology, mediating diverse functions including protein quality control, signal transduction, trafficking, and more. While molecular mechanisms of rhomboid activity have been well-characterized in invertebrate and cell-based systems, their physiological role in vertebrate development remains limited and continues to evolve. Here, we review recent advances in cell culture systems and vertebrate models that uncover the developmental and disease-relevant functions of rhomboid family members, including RHBDLs, iRhoms, PARL, and Derlins. We outline their roles in embryogenesis, tissue regeneration, neurodevelopment, and immune signaling, alongside their pathological involvement in cancer, neurodegeneration, and metabolic disorders. We also emphasize the limitations posed by early embryonic lethality in knockout models and advocate for tissue-specific vertebrate models to dissect rhomboid-dependent pathways in vivo. Understanding how rhomboid proteins coordinate developmental processes will not only reveal fundamental principles of membrane-associated processes, but also open new avenues for therapeutic targeting in disease.
菱形蛋白酶超家族包括蛋白酶和假蛋白酶，已成为膜生物学的核心调节因子，介导多种功能，包括蛋白质质量控制、信号转导、运输等。虽然菱形蛋白酶活性的分子机制在无脊椎动物和细胞系统中已得到充分表征，但其在脊椎动物发育中的生理作用仍然有限，并且仍在不断演变。在这里，我们回顾了细胞培养系统和脊椎动物模型的最新进展，这些进展揭示了菱形蛋白酶家族成员（包括RHBDL、iRhom、PARL和Derlin）与发育和疾病相关的功能。我们概述了它们在胚胎发生、组织再生、神经发育和免疫信号传导中的作用，以及它们在癌症、神经退行性疾病和代谢紊乱中的病理参与。我们还强调了基因敲除模型中早期胚胎致死性带来的局限性，并主张使用组织特异性脊椎动物模型在体内剖析菱形蛋白酶依赖性途径。了解菱形蛋白酶如何协调发育过程不仅将揭示膜相关过程的基本原理，还将为疾病的治疗靶点开辟新途径。
