bims-mirnam 2026-10-04 papers

Issue of 2026–10–04
three papers selected by
Hana Antonicka, McGill University

Nat Rev Drug Discov. 2026 Sep 29.

The cellular landscape of druggable RNA-binding proteins.

Gaia Di Timoteo, Benson M George, Omar Abdel-Wahab, Ryan A Flynn, Konstantinos Tzelepis.

RNA-binding proteins (RBPs) are involved in every step of RNA metabolism, from RNA processing and modification to translation and decay, and are also important for the function of non-coding RNAs. As such, RBPs are crucial in shaping cell identity and are central to the development of numerous diseases. Over the past decade, systematic efforts to explore the RNA interactome have expanded the RBP census as well as the landscape of potentially therapeutically targetable RBPs. More recently, certain RBPs have been shown to be present on the cell surface with cell-type and disease-associated specificities. These cell surface RBPs could potentially serve as biomarkers and immunotherapy targets in a variety of diseases. Here, we summarize established intracellular roles for RBPs, as well as their connections to disease with an emphasis on cancer. Moreover, we review the nascent field of cell surface RBPs and describe strategies to harness the cell surface localization of RBPs for the design and development of novel immunotherapeutic modalities.

DOI: https://doi.org/10.1038/s41573-026-01531-2

bioRxiv. 2026 Aug 24. pii: 2026.08.22.746448. [Epub ahead of print]

Kinetic Control of Nuclear-encoded Mitochondrial mRNA Localization and Local Translation.

Surbhi Sharma, Xuemei Wang, Steven Nguyen, Madeline E Rasband, Trinh T Tat, Prabha Chupal, Jen-Yun Chang, Eric L Van Nostrand, Daniel L Kiss, Aidan I Brown, Furqan M Fazal.

Most biological processes are dynamic, yet experimental methods predominantly rely on steady-state measurements to investigate their underlying mechanisms. RNA localization is a fundamental aspect of eukaryotic cell organization and is dynamically regulated by cells. While extensively studied in specialized cell types for a limited number of candidate RNAs, the general principles governing dynamic RNA localization at a transcriptome-wide scale remain largely unexplored. Existing transcriptome-wide studies provide only a static snapshot of RNAs residing in specific cellular locales, in part due to the limited availability of tools for probing cellular spatial organization at biologically relevant scales. Here, we leverage the high spatial (tens of nanometers) and temporal (minute) resolution of APEX-seq to quantitatively measure the dependence of RNA transport on molecular motors at a transcriptome-wide scale in living cells. We conducted these experiments in the context of the localization of mRNAs to the mitochondria, which are essential for cellular function. Our findings indicate that the majority of nuclear-encoded RNAs encoding mitochondrial proteins localize to the outer mitochondrial membrane (OMM) for local translation. We reveal a crucial role of retrograde dynein-based motor transport in RNA localization, demonstrating that its disruption severely impairs RNA targeting to the OMM. Time-resolved profiling of RNAs at the OMM revealed that localization is an active process, and even a brief disruption of transport for a few minutes results in a dramatic loss of localization. Moreover, we demonstrate that the translation efficiency (TE) of localized RNAs is a critical determinant of RNA localization in the context of motor-driven transport, as RNAs that delocalize following motor-transport perturbations exhibit lower TE. Using our temporal perturbation data, we also developed a spatiotemporal model that utilizes translation kinetics to capture key features of RNA localization dynamics at the OMM. Together, experiments and modeling suggest that the process of local translation at the OMM is kinetically controlled by the cell, and reveal an unappreciated mechanism by which active transport of RNAs enables cells to modulate their translation within minutes through RNA localization control. Our study demonstrates how simultaneously capturing the kinetics of hundreds of transcripts with minute resolution can uncover general principles of cellular and organelle organization. Together, these experiments and modeling reveal how active transport and translation jointly maintain the OMM-localized transcriptome. More broadly, they identify RNA localization to cellular membranes as a rapidly tunable mechanism for controlling local translation, even in non-polarized cells.

DOI: https://doi.org/10.64898/2026.08.22.746448

JACS Au. 2026 Sep 28. 6(9): 5439-5454

Development of High-Efficiency Mitochondrial Protease Targeting Chimeras (MtPTACs) for Targeted Degradation of POLRMT and Beyond.

Cong Chen, Lihua Liu, Xinnan Li, Yuning Shi, Jieya Zhou, Lijuan Huang, Liyue Zeng, Dazhi Feng, Yunyue Wang, Xinyang Nie, Quanyi Huang, Yifei Wu, Shaokang Pang, Jinyi Xu, Shengtao Xu, Hong Yao.

Despite the broad success of targeted protein degradation (TPD), achieving efficient degradation within mitochondria remains a challenge. Herein, we report a highly active degrader targeting human mitochondrial RNA polymerase (POLRMT) based on the Mitochondrial Protease Targeting Chimeras (MtPTACs) strategy. The lead compound, MTP-B1, is a highly potent MtPTAC to achieve essentially complete target degradation (D max > 98%) within 24 h at sub-micromolar concentrations. Mechanistically, MTP-B1 circumvents the compensatory transcriptional upregulation induced by POLRMT inhibitors and sustains downstream signaling suppression in washout assays. Remarkably, under the dosing regimens tested, MTP-B1 exhibited greater in vivo antitumor efficacy than the co-administration of a POLRMT inhibitor and a ClpP activator, highlighting the therapeutic potential of targeted protein degradation in mitochondria. These findings, further supported by the extension to a second target, dihydroorotate dehydrogenase (DHODH), provide high-efficiency MtPTACs as a powerful and generalizable modality for mitochondrial medicine.

Keywords: Mitochondrial ClpP protease; Mitochondrial Protease Targeting Chimeras (MtPTACs); OXPHOS; POLRMT; Targeted protein degradation

DOI: https://doi.org/10.1021/jacsau.6c01255