RAN binding protein 2 (RANBP2/Nup358) is a cytoplasmic filament nucleoporin involved in various cellular processes, such as nucleocytoplasmic transport and post-translational modifications. This review comprehensively discusses how dysregulation or mutation of RANBP2 contributes to human pathologies, and how the dynamic chromosomal region containing RANBP2 led to the appearance of the RGPD gene family during ape evolution.

RANBP2/Nup358 (Ran Binding Protein 2) is a nucleoporin and a key component of the nuclear pore complex. Through its multiple functions (e.g. SUMOylation, regulation of nucleocytoplasmic transport) and subcellular localizations (e.g. at the nuclear envelope, kinetochores, annulate lamellae), it is involved in many cellular processes. RANBP2 dysregulation or mutation leads to the development of human pathologies, such as Acute Necrotizing Encephalopathy 1 (ANE1), cancer, neurodegenerative diseases and it is also involved in viral infections. The chromosomal region containing the RANBP2 gene is highly dynamic, with high structural variation and recombination events that led to the appearance of a gene family called RGPD (RANBP2 and GCC2 Protein Domains), with multiple gene loss/duplication events during ape evolution. Although RGPD homoplasy and maintenance during evolution suggest they might confer an advantage to their hosts, their functions are still unknown and understudied. In this review, we discuss the appearance and importance of RANBP2 in metazoans and its function-related pathologies, caused by an alteration of its expression levels (through promotor activity, post-transcriptional or post-translational modifications), its localization or genetic mutations.

We consider the features of the nuclear lamina and NPC comparing humans, yeasts and trypanosomes. We discuss how those nuclear elements are structured in trypanosomes and how they differ from, or are conserved with other eukaryotic lineages. We also discuss the functional and evolutionary aspects of those fundamental elements of nuclear structure.

One of the remarkable features of eukaryotes is the nucleus, delimited by the nuclear envelope, a complex structure and home to the nuclear lamina and nuclear pore complex (NPC). For decades these structures were believed to be mainly architectural elements and, in the case of the NPC, simply facilitating nucleocytoplasmic trafficking. More recently the critical roles of the lamina, NPC and other nuclear envelope constituents in genome organisation, maintaining chromosomal domains and regulating gene expression have been recognised. Importantly, mutations in genes encoding lamina and NPC components lead to pathogenesis in humans, while in pathogenic protozoa disrupt the progression of normal development and expression of pathogenesis-related genes. Here we review features of the lamina and NPC across eukaryotes and discuss how these elements are structured in trypanosomes, protozoa of high medical and veterinary importance, highlighting lineage-specific and conserved aspects of nuclear organisation.

Autophagy is stimulated by starvation (amino acids and/or glucose deprivation) and growth factor limitation. In addition, mechanical forces are also positive regulators of autophagy. Growth factors and mechanical forces trigger signaling from the cell surface including from the primary cilium (PC) whereas nutrients directly act intracellularly. Many of the stimuli that control autophagy converge on the kinases mTOR and AMPK.

Macroautophagy is a lysosomal degradative pathway for intracellular macromolecules, protein aggregates and organelles. The formation of the autophagosome, a double membrane-bound structure that sequesters cargoes before their delivery to the lysosome, is regulated by several stimuli in multicellular organisms. Pioneering studies in rat liver showed the importance of amino acids, insulin and glucagon in controlling macroautophagy. Thereafter, many studies have deciphered the signaling pathways downstream of these biochemical stimuli to control autophagosome formation. Two signaling hubs have emerged: the kinase mTOR, in a complex at the surface of lysosomes which is sensitive to nutrients and hormones; and AMPK, which is sensitive to the cellular energetic status. Besides nutritional, hormonal and energetic fluctuations, many organs have to respond to mechanical forces (compression, stretching and shear stress). Recent studies have shown the importance of mechanotransduction in controlling macroautophagy. This regulation engages cell surface sensors, such as the primary cilium, in order to translate mechanical stimuli into biological responses.

This perspective discusses the challenges associated with nuclear pore complex (NPC) assembly and the need for quality control (QC) mechanisms that operate at various stages of an NPC's life: from QC mechanisms that keep individual nups assembly-competent prior to their incorporation in a new NPC and QC at the assembly site, to those that deal with damaged NPCs post-assembly.

The integrity of the nuclear envelope depends on the function of nuclear pore complexes (NPCs), transport channels that control macromolecular traffic between the nucleus and cytosol. The central importance of NPCs suggests the existence of quality control (QC) mechanisms that oversee their assembly and function. In this perspective, we emphasize the challenges associated with NPC assembly and the need for QC mechanisms that operate at various stages of an NPC's life. This includes cytosolic preassembly QC that helps enforce key nucleoporin–nucleoporin interactions and their ultimate stoichiometry in the NPC in addition to mechanisms that monitor aberrant fusion of the inner and outer nuclear membranes. Furthermore, we discuss whether and how these QC mechanisms may operate to sense faulty mature NPCs to facilitate their repair or removal. The so far uncovered mechanisms for NPC QC provide fertile ground for future research that not only benefits a better understanding of the vital role that NPCs play in cellular physiology but also how loss of NPC function and/or these QC mechanisms might be an input to aging and disease.

In this review, the authors detail and discuss recent literature documenting nuclear pore complex, nucleocytoplasmic transport, and nuclear envelope alterations in neurodegenerative disease.

Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

Nuclear pore complexes are multicomponent assemblies that support nucleocytoplasmic transport and contribute to gene regulation. Some nuclear pore components are also known to bind chromatin and affect gene expression in the nuclear interior, away from sites of transport. In this review, we discuss chromatin-binding functions of intranuclear nuclear pore proteins and highlight their identity as components of chromatin regulatory complexes.

Nuclear pore complexes are large multicomponent protein complexes that are embedded in the nuclear envelope, where they mediate nucleocytoplasmic transport. In addition to supporting transport, nuclear pore components, termed nucleoporins (Nups), can interact with chromatin and influence genome function. A subset of Nups can also localize to the nuclear interior and bind chromatin intranuclearly, providing an opportunity to investigate chromatin-associated functions of Nups outside of the transport context. This review focuses on the gene regulatory functions of such intranuclear Nups, with a particular emphasis on their identity as components of several chromatin regulatory complexes. Recent proteomic screens have identified Nups as interacting partners of active and repressive epigenetic machinery, architectural proteins, and DNA replication complexes, providing insight into molecular mechanisms via which Nups regulate gene expression programs. This review summarizes these interactions and discusses their potential functions in the broader framework of nuclear genome organization.

Recent studies utilising cryo-electron tomography and detailed analysis of the image data have revealed novel information on the membrane dynamics of autophagosome biogenesis, including the shape and dimensions of omegasomes, phagophores and autophagosomes, and their relationships with the organelles around them. This review summarises the findings of three recent papers revealing new exciting information on phagophore biogenesis.

Autophagosome biogenesis, from the appearance of the phagophore to elongation and closure into an autophagosome, is one of the long-lasting open questions in the autophagy field. Recent studies utilising cryo-electron tomography and detailed analysis of the image data have revealed new information on the membrane dynamics of these events, including the shape and dimensions of omegasomes, phagophores and autophagosomes, and their relationships with the organelles around them. One of the important predictions from the new results is that 60–80% of the autophagosome membrane area is delivered by direct lipid transfer or lipid synthesis. Cryo-electron tomography can be expected to provide new directions for autophagy research in the near future.

Ran-binding protein 2 (Ranbp2) is a molecular hub for nucleocytoplasmic transport. Ran-GTP-binding domains (RBDs) of Ranbp2 destabilize Ran-GTP from its cargoes, whereas small molecules against the cyclophilin domain (CY) regulate Ranbp2 CY's moonlighting activity on client substrates. Ranbp2 haploinsufficiency protects retinal pigment epithelium and photoreceptors against phototoxicity, whereas Ranbp2 loss in motoneurons triggers amyotrophic lateral sclerosis-like behavior (e.g., paralysis).

Nucleocytoplasmic transport comprises the multistep assembly, transport, and disassembly of protein and RNA cargoes entering and exiting nuclear pores. Accruing evidence supports that impairments to nucleocytoplasmic transport are a hallmark of neurodegenerative diseases. These impairments cause dysregulations in nucleocytoplasmic partitioning and proteostasis of nuclear transport receptors and client substrates that promote intracellular deposits – another hallmark of neurodegeneration. Disturbances in liquid–liquid phase separation (LLPS) between dense and dilute phases of biomolecules implicated in nucleocytoplasmic transport promote micrometer-scale coacervates, leading to proteinaceous aggregates. This Review provides historical and emerging principles of LLPS at the interface of nucleocytoplasmic transport, proteostasis, aging and noxious insults, whose dysregulations promote intracellular aggregates. E3 SUMO-protein ligase Ranbp2 constitutes the cytoplasmic filaments of nuclear pores, where it acts as a molecular hub for rate-limiting steps of nucleocytoplasmic transport. A vignette is provided on the roles of Ranbp2 in nucleocytoplasmic transport and at the intersection of proteostasis in the survival of photoreceptor and motor neurons under homeostatic and pathophysiological environments. Current unmet clinical needs are highlighted, including therapeutics aiming to manipulate aggregation-dissolution models of purported neurotoxicity in neurodegeneration.

Significant progress has been made in understanding autophagosome formation and the roles of autophagy-related proteins. This article addresses three less-understood steps of autophagy in yeast: phagophore closure, autophagosome maturation, and autophagosome fusion with the vacuole. Current insights are discussed to shed light on these steps.

Macroautophagy, hereafter referred to as autophagy, is a complex process in which multiple membrane-remodeling events lead to the formation of a cisterna known as the phagophore, which then expands and closes into a double-membrane vesicle termed the autophagosome. During the past decade, enormous progress has been made in understanding the molecular function of the autophagy-related proteins and their role in generating these phagophores. In this Review, we discuss the current understanding of three membrane remodeling steps in autophagy that remain to be largely characterized; namely, the closure of phagophores, the maturation of the resulting autophagosomes into fusion-competent vesicles, and their fusion with vacuoles/lysosomes. Our review will mainly focus on the yeast Saccharomyces cerevisiae, which has been the leading model system for the study of molecular events in autophagy and has led to the discovery of the major mechanistic concepts, which have been found to be mostly conserved in higher eukaryotes.