BioEssays最新文献

Dynamin superfamily proteins (DSPs) are large GTPases that play crucial roles in membrane remodeling processes, including vesicle uptake, mitochondrial fission, and opposing fusion events. Among them, dynamin and dynamin-related protein 1 (Drp1) share a conserved domain architecture, yet exhibit unique structural and regulatory features that tailor their functions. This review explores the conformational rearrangements of the mammalian fission DSPs, dynamin and Drp1, focusing on their dimeric and tetrameric structures, lipid-bound assemblies, and key regulatory elements that drive membrane constriction. Structural biology methods, including x-ray crystallography and cryo-electron microscopy, have provided insight into the mechanism of activation and constriction of these DSPs, revealing how domain interactions and intrinsically disordered regions regulate self-assembly and enzymatic activity. We briefly examine the role of sequence modifications and partner proteins in modulating DSP function, highlighting the impact of regulatory factors on their respective cellular functions. An ongoing goal is to better understand the molecular mechanisms governing the transitions from a pre-assembled cytosolic state to a self-assembled state for dynamin and Drp1 on membranes, which provides a foundation for studying subsequent helical constriction. This insight will enhance our knowledge of organelle dynamics and provide new avenues for therapeutic interventions targeting DSP-related pathologies.

Primary cilia are customized subcellular signaling compartments leveraged to detect signals in diverse physiological contexts. Although prevalent throughout mammalian tissues, primary cilia are not universal. Many non-ciliated cells derive from developmental lineages that include ciliated progenitors; however, little is known about how primary cilia are lost as cells differentiate. Here, we examine how ciliated and non-ciliated states emerge during development and are actively maintained. We highlight several pathways for primary cilia loss, including cilia resorption in pre-mitotic cells, cilia deconstruction in post-mitotic cells, cilia shortening via remodeling, and cilia disassembly preceding multiciliogenesis. Lack of ciliogenesis is known to decrease primary cilia frequency and cause ciliopathies. Failure to maintain cilia can also cause primary cilia to be absent. Conversely, defects in primary cilia suppression or disassembly can lead to the presence of primary cilia in non-ciliated cells. We examine how changes in ciliation states could contribute to tumorigenesis and neurodegeneration.

Mitosis is a crucial phase of the cell cycle, during which several mechanisms work together to ensure accurate chromosome segregation and to eliminate defective cells if errors occur. One key mechanism is the spindle assembly checkpoint (SAC), which upon mitotic errors—such as those induced by genetic mutations, drug treatments, or environmental stresses—arrest cells in mitosis. Arrested cells may undergo apoptosis during mitosis or eventually exit mitosis even if the damage remains unrepaired. Mitotic exit is driven by a reduction in cyclin B1 levels, regulated during mitosis by multiple mechanisms affecting both its synthesis and degradation. Strikingly, cells harboring the tumor suppressor p53 can monitor the duration of mitosis and encode this information as a form of “mitotic memory”. This memory influences the fate of daughter cells after mitotic exit by inducing G1 arrest through p53-dependent expression of the cyclin-dependent kinase (CDK) inhibitor p21. Recent studies have proposed mechanisms by which cyclin B1 levels are regulated during mitotic arrest and how p53 promotes mitotic-arrest-dependent transcription of p21 in G1. These findings indicate that both the expression of regulators that control mitotic duration and the activity of proteins that monitor the duration of mitosis and halt proliferation work together to determine cell fate following mitotic errors. Understanding these mechanisms offers valuable insights for cancer therapy, particularly regarding the strategic application of antimitotic agents.

In article 70044 Lana Kostic and Nick Barker review the evolving understanding of stem cell dynamics in the esophagus, with a focus on their roles in tissue homeostasis and cancer development. Challenging earlier models that proposed a uniform basal progenitor layer, recent findings suggest a heterogeneous pool of stem and progenitor cells with distinct phenotypic and functional traits. This cellular diversity may influence individual susceptibility to esophageal cancer, which can arise from random mutations or cancer stem cell activity. The authors highlight how advances in single-cell technologies and organoid models are reshaping perspectives on esophageal biology and offer promising avenues for therapeutic innovation. By re-evaluating stem cell identity and behavior, the article underscores the complexity of epithelial maintenance and the multifactorial nature of cancer initiation in the esophagus.

Recent advances in genomics uncovered a large number of microproteins, which are peptides of less than 100 amino-acids encoded by small open reading frames. In contrast to their identification, the validation of the functions of microproteins remains challenging. Especially, what are their biological functions in the cell and how this relates to disease conditions are still largely unknown. Although microproteins ensure a plethora of cellular functions, recent evidence demonstrate that they may disproportionately affect cellular metabolism. In this review, we will address the roles of mitochondrial-targeted microproteins, and especially how this class of protein regulates neuronal metabolism in neurodevelopment and neurodegeneration, and may contribute to axonal and dendritic metabolic disorders.

Although the inner nuclear membrane (INM) is generally considered to be continuous with the outer nuclear membrane (ONM) and connected to the remaining endoplasmic reticulum (ER), it has been well recognized that it is functionally distinct, having a unique protein composition. It has increasingly been recognized, however, that the INM also differs from the ONM and the other ER domains in its lipid composition. It is an intriguing proposition that the unique lipid profile of the INM is intricately linked to its specialized functions related to the nuclear events. Despite rapid progress in recent years in our understanding of the unique lipid profile of the INM and its role in the control of nuclear functions, there is a lot that remains to be understood. This review summarizes recent advances in characterizing the INM lipid composition and lipid synthetic pathways including their possible roles in the control of nuclear functions. Additionally, it discusses current challenges and areas deserving further investigation.

K. C. Sule, M. Nakamura, and S. M. Parkhurst, “Nuclear Envelope Budding: Getting Large Macromolecular Complexes Out of the Nucleus,” BioEssays 46 (2024): 2300182.

In this article, reference [85] was incorrect. The correct reference should be:

[85] J. W. Park, E. J. Lee, E. Moon, et al., “Orthodenticle Homeobox 2 is Transported to Lysosomes by Nuclear Budding Vesicles,” Nature Communications 14, no. 1 (2023): 1111, https://doi.org/10.1038/s41467-023-36697-5. Epub 20230227.

We apologize for this error.

Migrating neurons form a growth cone at the tip of their leading process. This specialized structure shares striking anatomical and functional similarities with axonal growth cones. We hypothesize that both cones respond to common extracellular cues and direct neuronal migration and axon extension, respectively, through analogous mechanisms. Guidance cues provide growth cones with attractive or repulsive signals to direct them towards their targets. By binding to specific receptors on growth cones, these cues trigger intracellular signaling pathways that reorganize the cytoskeleton and propel neurons or axons in precise directions. Notably, many of the receptors that mediate axon guidance are also present in the growth cones of migrating neurons, reinforcing the idea of a conserved molecular machinery. Elucidating the molecular mechanisms underlying growth cone dynamics in migrating neurons promises to deepen our understanding of neuronal development, and to pave the way for new regenerative therapies aimed at promoting neuronal migration.