bims-nucpor 2022-03-27 papers

bims-nucpor

Biomed News

on Nuclear pore complex and nucleoporins in stress, aging and disease

Issue of 2022‒03‒27
six papers selected by
Sara Mingu
Johannes Gutenberg University

On the nuclear pore complex and its emerging role in cellular mechanotransduction.
Function of Nuclear Pore Complexes in Regulation of Plant Defense Signaling.
Biophysical characterization of the interaction of Atg8 with a disordered region of Nup159 involved in selective autophagy of the nuclear pore complex.
A Multisensory Network Drives Nuclear Mechanoadaptation.
Atomic resolution dynamics of cohesive interactions in phase-separated Nup98 FG domains.
C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm.

APL Bioeng. 2022 Mar;6(1): 011504

On the nuclear pore complex and its emerging role in cellular mechanotransduction.

Atsushi Matsuda, Mohammad R K Mofrad.

The nuclear pore complex (NPC) is a large protein assembly that perforates the nuclear envelope and provides a sole gateway for traffic between the cytoplasm and the nucleus. The NPC controls the nucleocytoplasmic transport by selectively allowing cargoes such as proteins and mRNA to pass through its central channel, thereby playing a vital role in protecting the nuclear component and regulating gene expression and protein synthesis. The selective transport through the NPC originates from its exquisite molecular structure featuring a large scaffold and the intrinsically disordered central channel domain, but the exact mechanism underlying the selective transport remains elusive and is the subject of various, often conflicting, hypotheses. Moreover, recent studies have suggested a new role for the NPC as a mechanosensor, where the NPC changes its channel diameter depending on the nuclear envelope tension, altering the molecular transportability through this nanopore. In this mini-review, we summarize the current understandings of the selective nature of the NPC and discuss its emerging role in cellular mechanotransduction.

DOI: https://doi.org/10.1063/5.0080480
Int J Mol Sci. 2022 Mar 11. pii: 3031. [Epub ahead of print]23(6):

Function of Nuclear Pore Complexes in Regulation of Plant Defense Signaling.

Xi Wu, Junyou Han, Changkui Guo.

  In eukaryotes, the nucleus is the regulatory center of cytogenetics and metabolism, and it is critical for fundamental biological processes, including DNA replication and transcription, protein synthesis, and biological macromolecule transportation. The eukaryotic nucleus is surrounded by a lipid bilayer called the nuclear envelope (NE), which creates a microenvironment for sophisticated cellular processes. The NE is perforated by the nuclear pore complex (NPC), which is the channel for biological macromolecule bi-directional transport between the nucleus and cytoplasm. It is well known that NPC is the spatial designer of the genome and the manager of genomic function. Moreover, the NPC is considered to be a platform for the continual adaptation and evolution of eukaryotes. So far, a number of nucleoporins required for plant-defense processes have been identified. Here, we first provide an overview of NPC organization in plants, and then discuss recent findings in the plant NPC to elaborate on and dissect the distinct defensive functions of different NPC subcomponents in plant immune defense, growth and development, hormone signaling, and temperature response. Nucleoporins located in different components of NPC have their unique functions, and the link between the NPC and nucleocytoplasmic trafficking promotes crosstalk of different defense signals in plants. It is necessary to explore appropriate components of the NPC as potential targets for the breeding of high-quality and broad spectrum resistance crop varieties.

Keywords:  biological function; defense signaling; nuclear pore complex; nucleoporin; structure

DOI:  https://doi.org/10.3390/ijms23063031
Biochem Biophys Res Commun. 2022 Mar 12. pii: S0006-291X(22)00388-6. [Epub ahead of print]604 172-178

Biophysical characterization of the interaction of Atg8 with a disordered region of Nup159 involved in selective autophagy of the nuclear pore complex.

RyeongHyeon Kim, Junseock Koh.

  A functional proteome in the cell is maintained by coordinate regulation of biogenesis, folding, and degradation of cellular proteins. Although the degradation pathways have been extensively characterized for various substrates, it remains elusive how large multiprotein complexes are selectively degraded. Recent investigations have discovered selective autophagic degradation of the yeast Nuclear Pore Complex (NPC) consisting of ∼500 proteins and mediating selective nucleocytoplasmic transport. To understand the underlying molecular mechanism of NPC-phagy, we performed biophysical characterization of the interaction between Atg8 and an intrinsically disordered region (IDR) of Nup159 involved in the initial recognition step. In particular, from the systematic isothermal titration calorimetry (ITC) experiments, we determined the thermodynamic parameters and discovered a significant negative heat capacity change (ΔCp°) for the interaction. Furthermore, the heat capacity change becomes more negative at higher temperatures, yielding a negative curvature in the observed enthalpy change (ΔH°) with respect to temperature. This thermodynamic feature was analyzed in terms of coupling between binding and conformational equilibria of Atg8 and/or Nup159 IDR. We interpret the coupled conformational equilibria as disorder-to-order transitions or local stabilizations of Nup159 IDR and/or partially unfolded Atg8 upon binding. A potential impact of the proposed coupling in the initial step of NPC-phagy is discussed. In a broader view, our study demonstrates that a negative curvature of ΔH° can be used as a probe for conformational selection processes in the interactions of IDRs with their target proteins.

Keywords:  Atg8; Coupled conformational change; Heat capacity change; Intrinsically disordered region; Nucleoporin; Selective autophagy

DOI:  https://doi.org/10.1016/j.bbrc.2022.03.056
Biomolecules. 2022 Mar 04. pii: 404. [Epub ahead of print]12(3):

A Multisensory Network Drives Nuclear Mechanoadaptation.

Asier Echarri.

  Cells have adapted to mechanical forces early in evolution and have developed multiple mechanisms ensuring sensing of, and adaptation to, the diversity of forces operating outside and within organisms. The nucleus must necessarily adapt to all types of mechanical signals, as its functions are essential for virtually all cell processes, many of which are tuned by mechanical cues. To sense forces, the nucleus is physically connected with the cytoskeleton, which senses and transmits forces generated outside and inside the cell. The nuclear LINC complex bridges the cytoskeleton and the nuclear lamina to transmit mechanical information up to the chromatin. This system creates a force-sensing macromolecular complex that, however, is not sufficient to regulate all nuclear mechanoadaptation processes. Within the nucleus, additional mechanosensitive structures, including the nuclear envelope and the nuclear pore complex, function to regulate nuclear mechanoadaptation. Similarly, extra nuclear mechanosensitive systems based on plasma membrane dynamics, mechanotransduce information to the nucleus. Thus, the nucleus has the intrinsic structural components needed to receive and interpret mechanical inputs, but also rely on extra nuclear mechano-sensors that activate nuclear regulators in response to force. Thus, a network of mechanosensitive cell structures ensures that the nucleus has a tunable response to mechanical cues.

Keywords:  lipid bilayer mechano-sensing; mechano-transduction; mechanosensitive molecules; nuclear envelope; nucleus

DOI:  https://doi.org/10.3390/biom12030404
Nat Commun. 2022 Mar 21. 13(1): 1494

Atomic resolution dynamics of cohesive interactions in phase-separated Nup98 FG domains.

Eszter E Najbauer, Sheung Chun Ng, Christian Griesinger, Dirk Görlich, Loren B Andreas.

Cohesive FG domains assemble into a condensed phase forming the selective permeability barrier of nuclear pore complexes. Nanoscopic insight into fundamental cohesive interactions has long been hampered by the sequence heterogeneity of native FG domains. We overcome this challenge by utilizing an engineered perfectly repetitive sequence and a combination of solution and magic angle spinning NMR spectroscopy. We map the dynamics of cohesive interactions in both phase-separated and soluble states at atomic resolution using TROSY for rotational correlation time (TRACT) measurements. We find that FG repeats exhibit nanosecond-range rotational correlation times and remain disordered in both states, although FRAP measurements show slow translation of phase-separated FG domains. NOESY measurements enable the direct detection of contacts involved in cohesive interactions. Finally, increasing salt concentration and temperature enhance phase separation and decrease local mobility of FG repeats. This lower critical solution temperature (LCST) behaviour indicates that cohesive interactions are driven by entropy.

DOI: https://doi.org/10.1038/s41467-022-28821-8
Sci Rep. 2022 Mar 21. 12(1): 4799

C9orf72 dipeptides disrupt the nucleocytoplasmic transport machinery and cause TDP-43 mislocalisation to the cytoplasm.

Sarah Ryan, Sara Rollinson, Eleanor Hobbs, Stuart Pickering-Brown.

A repeat expansion in C9orf72 is the major cause of both frontotemporal dementia and amyotrophic lateral sclerosis, accounting for approximately 1 in 12 cases of either disease. The expansion is translated to produce five dipeptide repeat proteins (DPRs) which aggregate in patient brain and are toxic in numerous models, though the mechanisms underlying this toxicity are poorly understood. Recent studies highlight nucleocytoplasmic transport impairments as a potential mechanism underlying neurodegeneration in C9orf72-linked disease, although the contribution of DPRs to this remains unclear. We expressed DPRs in HeLa cells, in the absence of repeat RNA. Crucially, we expressed DPRs at repeat-lengths found in patients (> 1000 units), ensuring our findings were relevant to disease. Immunofluorescence imaging was used to investigate the impact of each DPR on the nucleus, nucleocytoplasmic transport machinery and TDP-43 localisation. DPRs impaired the structural integrity of the nucleus, causing nuclear membrane disruption and misshapen nuclei. Ran and RanGAP, two proteins required for nucleocytoplasmic transport, were also mislocalised in DPR-expressing cells. Furthermore, DPRs triggered mislocalisation of TDP-43 to the cytoplasm, and this occurred in the same cells as Ran and RanGAP mislocalisation, suggesting a potential link between DPRs, nucleocytoplasmic transport impairments and TDP-43 pathology.

DOI: https://doi.org/10.1038/s41598-022-08724-w