Shieldin, including SHLD1, SHLD2, SHLD3 and REV7, functions as a bridge linking 53BP1-RIF1 and single-strand DNA to suppress the DNA termini nucleolytic resection during non-homologous end joining (NHEJ). However, the mechanism of shieldin assembly remains unclear. Here we present the crystal structure of the SHLD3-REV7-SHLD2 ternary complex and reveal an unexpected C (closed)-REV7-O (open)-REV7 conformational dimer mediated by SHLD3. We show that SHLD2 interacts with O-REV7 and the N-terminus of SHLD3 by forming β sheet sandwich. Disruption of the REV7 conformational dimer abolishes the assembly of shieldin and impairs NHEJ efficiency. The conserved FXPWFP motif of SHLD3 binds to C-REV7 and blocks its binding to REV1, which excludes shieldin from the REV1/Pol ζ translesion synthesis (TLS) complex. Our study reveals the molecular architecture of shieldin assembly, elucidates the structural basis of the REV7 conformational dimer, and provides mechanistic insight into orchestration between TLS and NHEJ.

The folded mitochondria inner membrane-cristae is the structural foundation for oxidative phosphorylation (OXPHOS) and energy production. By mechanically simulating mitochondria morphogenesis, we speculate that efficient sculpting of the cristae is organelle non-autonomous. It has long been inferred that folding requires buckling in living systems. However, the tethering force for cristae formation and regulation has not been identified. Combining electron tomography, proteomics strategies, super resolution live cell imaging and mathematical modeling, we reveal that the mitochondria localized actin motor-myosin 19 (Myo19) is critical for maintaining cristae structure, by associating with the SAM-MICOS super complex. We discover that depletion of Myo19 or disruption of its motor activity leads to altered mitochondria membrane potential and decreased OXPHOS. We propose that Myo19 may act as a mechanical tether for effective ridging of the mitochondria cristae, thus sustaining the energy homeostasis essential for various cellular functions.

Despite the availability of a series of classical antibiotic drugs, bacterial infections continue to represent a significant and urgent threat to global human health. The emergence of drug-resistant bacteria and the slow pace of antibiotic development have rendered current treatment methods inadequate in meeting the clinical demands of bacterial infections. Consequently, there is an increasingly urgent and vital need for the development of safe, efficient, and alternative novel antimicrobial agents in the medical and healthcare field. Over the past five years, there has been a notable expansion in the field of nanomedicine with regard to the prevention and control of infectious diseases. The objective of this article is to provide a comprehensive review of the latest research developments in the field of metal nanomaterials for medical antimicrobial therapy. We begin by delineating the gravity of the bacterial infection crisis, subsequently undertaking a comprehensive examination of the potential mechanisms through which nanoparticles may combat bacterial infections and the specific applications of these nanomaterials in the treatment of diverse infectious diseases. In conclusion, we eagerly anticipate the future development directions of metal nanomaterials in the field of antimicrobial therapy. We believe that with continuous technological advancements and innovations, this field will make even more outstanding contributions to safeguarding human health and well-being.

Protein drugs are of great importance in maintaining the normal functioning of living organisms. Indeed, they have been instrumental in combating tumors and genetic diseases for decades. Among these pharmaceutical agents, those that target intracellular components necessitate the use of therapeutic proteins to exert their effects within the targeted cells. However, the use of protein drugs is limited by their short half-life and potential adverse effects in the physiological environment. The advent of nanoparticles offers a promising avenue for prolonging the half-life of protein drugs. This is achieved by encapsulating proteins, thereby safeguarding their biological activity and ensuring precise delivery into cells. This nanomaterial-based intracellular protein drug delivery system mitigates the rapid hydrolysis and unwarranted diffusion of proteins, thereby minimizing potential side effects and circumventing the limitations inherent in traditional techniques like electroporation. This review examines established protein drug delivery systems, including those based on polymers, liposomes, and protein nanoparticles. We delve into the operational principles and transport mechanisms of nanocarriers, discussing the various considerations essential for designing cutting-edge delivery platforms. Additionally, we investigate innovative designs and applications of traditional cytosolic protein delivery systems in medical research and clinical practice, particularly in areas like tumor treatment, gene editing and fluorescence imaging. This review sheds light on the current restrictions of protein delivery systems and anticipates future research avenues, aiming to foster the continued advancement in this field.