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A new system to monitor the effects of nucleosome depletion in Xenopus egg extracts reveals that nucleosomes are required for spindle assembly and for recruitment of nuclear pore complex (NPC) components to the nuclear envelope for NPC formation. Nucleosomes are the fundamental unit of chromatin, but analysis of transcription-independent nucleosome functions has been complicated by the gene-expression changes resulting from histone manipulation. Here we solve this dilemma by developing Xenopus laevis egg extracts deficient for nucleosome formation and by analyzing the proteomic landscape and behavior of nucleosomal chromatin and nucleosome-free DNA. We show that although nucleosome-free DNA can recruit nuclear-envelope membranes, nucleosomes are required for spindle assembly and for formation of the lamina and of nuclear pore complexes (NPCs). We show that, in addition to the Ran G-nucleotide exchange factor RCC1, ELYS, the initiator of NPC formation, fails to associate with naked DNA but directly binds histone H2A–H2B dimers and nucleosomes. Tethering ELYS and RCC1 to DNA bypasses the requirement for nucleosomes in NPC formation in a synergistic manner. Thus, the minimal essential function of nucleosomes in NPC formation is to recruit RCC1 and ELYS.

Accurate chromosome segregation during mitosis requires the physical separation of sister chromatids before nuclear envelope reassembly (NER). However, how these two processes are coordinated remains unknown. Here, we identified a conserved feedback control mechanism that delays chromosome decondensation and NER in response to incomplete chromosome separation during anaphase. A midzone-associated Aurora B gradient was found to monitor chromosome position along the division axis and to prevent premature chromosome decondensation by retaining Condensin I. PP1/PP2A phosphatases counteracted this gradient and promoted chromosome decondensation and NER. Thus, an Aurora B gradient appears to mediate a surveillance mechanism that prevents chromosome decondensation and NER until effective separation of sister chromatids is achieved. This allows the correction and reintegration of lagging chromosomes in the main nuclei before completion of NER.

Human TOR1AIP1 encodes LAP1, a nuclear envelope protein expressed in most human tissues, which has been linked to various biological processes and human diseases. The clinical spectrum of diseases related to mutations in TOR1AIP1 is broad, including muscular dystrophy, congenital myasthenic syndrome, cardiomyopathy, and multisystemic disease with or without progeroid features. Although rare, these recessively inherited disorders often lead to early death or considerable functional impairment. Developing a better understanding of the roles of LAP1 and mutant TOR1AIP1-associated phenotypes is paramount to allow therapeutic development. To facilitate further studies, this review provides an overview of the known interactions of LAP1 and summarizes the evidence for the function of this protein in human health. We then review the mutations in the TOR1AIP1 gene and the clinical and pathological characteristics of subjects with these mutations. Lastly, we discuss challenges to be addressed in the future.

The nuclear envelope (NE), a protective membrane bordering the nucleus, is composed of highly specialized proteins that are indispensable for normal cellular activity. Lamina-associated polypeptide 1 (LAP1) is a NE protein whose functions are just beginning to be unveiled. The fact that mutations causing LAP1 deficiency are extremely rare and pathogenic is indicative of its paramount importance to preserving human health, anticipating that LAP1 might have a multifaceted role in the cell. Mapping the LAP1 protein interactome is, thus, imperative to achieve an integrated view of its potential biological properties. To this end, we employed in silico- and mass spectrometry-based approaches to identify candidate LAP1-interacting proteins, whose functional attributes were subsequently characterized using bioinformatics tools. Our results reveal the complex and multifunctional network of protein–protein interactions associated to LAP1, evidencing a strong interconnection between LAP1 and cellular processes as diverse as chromatin and cytoskeleton organization, DNA repair, RNA processing and translation, as well as protein biogenesis and turnover, among others. Novel interactions between LAP1 and DNA repair proteins were additionally validated, strengthening the previously proposed involvement of LAP1 in the maintenance of genomic stability. Overall, this study reaffirms the biological relevance of LAP1 and the need to deepen our knowledge about this NE protein, providing new insights about its potential functional partners that will help guiding future research towards a mechanistic understanding of LAP1’s functioning.

The nuclear envelope (NE) is a fundamental structure of the nucleus and plays an important role in nuclear morphology through the strict regulation of NE protein function. Beyond its physical barrier function between nucleoplasm and cytoplasm, recent studies of the plant NE have provided novel insights into basic aspects of nuclear morphology as well as cellular organization. In this review, we focus on plant NE proteins that have emerged from recent studies in nuclear morphology, and we discuss their physiological functions in cellular activities. A better understanding of the NE protein functions should provide key insights into the physiological significance of proper nuclear structure in plants.

At the nuclear periphery, associations of chromatin with the nuclear lamina through lamina-associated domains (LADs) aid functional organization of the genome. We review the organization of LADs and provide evidence of LAD heterogeneity from cell ensemble and single-cell data. LADs are typically repressive environments in the genome; nonetheless, we discuss findings of lamin interactions with regulatory elements of active genes, and the role lamins may play in genome regulation. We address the relationship between LADs and other genome organizers, and the involvement of LADs in laminopathies. The current data lay the basis for future studies on the significance of lamin-chromatin interactions in health and disease.

During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival.

Endosomal sorting complexes required for transport (ESCRTs) are key membrane remodellers, which drive the budding, scission and sealing of various cellular membranes. Accordingly, ongoing research focuses on how ESCRTs mediate a wide-range of cellular processes, including cytokinesis, endosome maturation, autophagy, membrane repair and viral replication.

Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause Emery–Dreifuss muscular dystrophy, congenital muscular dystrophy and other diseases collectively known as laminopathies. The mechanisms responsible for these diseases remain incompletely understood. Using three mouse models of muscle laminopathies and muscle biopsies from individuals with LMNA -related muscular dystrophy, we found that Lmna mutations reduced nuclear stability and caused transient rupture of the NE in skeletal muscle cells, resulting in DNA damage, DNA damage response activation and reduced cell viability. NE and DNA damage resulted from nuclear migration during skeletal muscle maturation and correlated with disease severity in the mouse models. Reduction of cytoskeletal forces on the myonuclei prevented NE damage and rescued myofibre function and viability in Lmna mutant myofibres, indicating that myofibre dysfunction is the result of mechanically induced NE damage. Taken together, these findings implicate mechanically induced DNA damage as a pathogenic contributor to LMNA skeletal muscle diseases. Lamin mutations responsible for muscular dystrophy are shown to reduce nuclear envelope stability, resulting in mechanically induced nuclear envelope rupture, DNA damage and activation of DNA damage response pathways that lead to muscle cell death. Preventing nuclear envelope damage by reducing cytoskeletal forces on the nucleus improves muscle fibre health and function.

In yeast, the novel protein Atg40 is enriched in the cortical and cytoplasmic endoplasmic reticulum (ER), and loads these ER subdomains into autophagosomes to facilitate ER autophagy; Atg39 localizes to the perinuclear ER and induces autophagic sequestration of part of the nucleus, thus ensuring cell survival under nitrogen-deprived conditions. ER-phagy receptors mapped The endoplasmic reticulum (ER) is a complex network of membranes involved in protein and lipid synthesis, ion homeostasis, protein quality control and organelle communication. It is also a source of membrane-bounded vesicles called autophagosomes, the vehicles for the self-digesting cellular process of autophagy. Two papers published online this week [in this issue of Nature] show how the ER itself is targeted for degradation by autophagy — a process that could ensure constant ER turnover in response to cellular requirements. Ivan Dikic and coworkers find the protein FAM134B is an ER-resident receptor that facilitates 'ER-phagy'. Downregulation of this protein — mutations of which can cause sensory neuropathy in humans — resulted in expanded ER structures and degeneration of mouse sensory neurons. Hitoshi Nakatogawa and colleagues show that the same phenomenon is conserved in yeast, where Atg40 is enriched in the cortical and cytoplasmic ER, loading these ER subdomains into autophagosomes. A further ER-phagy receptor, Atg39, localizes to the perinuclear ER (or the nuclear envelope) and induces autophagic sequestration of a part of the nucleus, thus ensuring cell survival under nitrogen-deprived conditions. Macroautophagy (hereafter referred to as autophagy) degrades various intracellular constituents to regulate a wide range of cellular functions, and is also closely linked to several human diseases 1 , 2 . In selective autophagy, receptor proteins recognize degradation targets and direct their sequestration by double-membrane vesicles called autophagosomes, which transport them into lysosomes or vacuoles 3 . Although recent studies have shown that selective autophagy is involved in quality/quantity control of some organelles, including mitochondria and peroxisomes 4 , it remains unclear how extensively it contributes to cellular organelle homeostasis. Here we describe selective autophagy of the endoplasmic reticulum (ER) and nucleus in the yeast Saccharomyces cerevisiae . We identify two novel proteins, Atg39 and Atg40, as receptors specific to these pathways. Atg39 localizes to the perinuclear ER (or the nuclear envelope) and induces autophagic sequestration of part of the nucleus. Atg40 is enriched in the cortical and cytoplasmic ER, and loads these ER subdomains into autophagosomes. Atg39-dependent autophagy of the perinuclear ER/nucleus is required for cell survival under nitrogen-deprivation conditions. Atg40 is probably the functional counterpart of FAM134B, an autophagy receptor for the ER in mammals that has been implicated in sensory neuropathy 5 . Our results provide fundamental insight into the pathophysiological roles and mechanisms of ‘ER-phagy’ and ‘nucleophagy’ in other organisms.