bims-nucpor 2022-12-04 papers

Issue of 2022–12–04
four papers selected by
Sara Mingu, Johannes Gutenberg University

J Parasit Dis. 2022 Dec;46(4): 1176-1191

An introduction to dynamic nucleoporins in Leishmania species: Novel targets for tropical-therapeutics.

Amit Kumar Dubey, Prakash Kumar, Debabrata Mandal, V Ravichandiran, Shubhankar Kumar Singh.

As an ailment, leishmaniasis is still an incessant challenge in neglected tropical diseases and neglected infections of poverty worldwide. At present, the diagnosis and treatment to combat Leishmania tropical infections are not substantial remedies and require advanced & specific research. Therefore, there is a need for a potential novel target to overcome established medicament modalities' limitations in pathogenicity. In this review, we proposed a few ab initio findings in nucleoporins of nuclear pore complex in Leishmania sp. concerning other infectious protists. So, through structural analysis and dynamics studies, we hypothesize the nuclear pore molecular machinery & functionality. The gatekeepers Nups, export of mRNA, mitotic spindle formation are salient features in cellular mechanics and this is regulated by dynamic nucleoporins. Here, diverse studies suggest that Nup93/NIC96, Nup155/Nup144, Mlp1/Mlp2/Tpr of Leishmania Species can be a picked out marker for diagnostic, immune-modulation, and novel drug targets. In silico prediction of nucleoporin-functional interactors such as NUP54/57, RNA helicase, Ubiquitin-protein ligase, Exportin 1, putative T-lymphocyte triggering factor, and 9 uncharacterized proteins suggest few more noble targets. The novel drug targeting to importins/exportins of Leishmania sp. and defining mechanism of Leptomycin-B, SINE compounds, Curcumins, Selinexor can be an arc-light in therapeutics. The essence of the review in Leishmania's nucleoporins is to refocus our research on noble molecular targets for tropical therapeutics.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12639-022-01515-0.

Keywords: Importins/exportins; Leishmaniasis; Nuclear localization signal; Nuclear pore complex; Nuclear transport inhibitors; Nucleoporins

DOI: https://doi.org/10.1007/s12639-022-01515-0

Front Cell Dev Biol. 2022 ;10 1041938

Non-transport roles of nuclear import receptors: In need of the right balance.

Michela Damizia, Ludovica Altieri, Patrizia Lavia.

Nuclear import receptors ensure the recognition and transport of proteins across the nuclear envelope into the nucleus. In addition, as diverse processes as mitosis, post-translational modifications at mitotic exit, ciliogenesis, and phase separation, all share a common need for regulation by nuclear import receptors - particularly importin beta-1 and importin beta-2/transportin - independent on nuclear import. In particular, 1) nuclear import receptors regulate the mitotic spindle after nuclear envelope breakdown, 2) they shield cargoes from unscheduled ubiquitination, regulating their timely proteolysis; 3) they regulate ciliary factors, crucial to cell communications and tissue architecture during development; and 4) they prevent phase separation of toxic proteins aggregates in neurons. The balance of nuclear import receptors to cargoes is critical in all these processes, albeit in opposite directions: overexpression of import receptors, as often found in cancer, inhibits cargoes and impairs downstream processes, motivating the therapeutic design of specific inhibitors. On the contrary, elevated expression is beneficial in neuronal contexts, where nuclear import receptors are regarded as potential therapeutic tools in counteracting the formation of aggregates that may cause neurodegeneration. This paradox demonstrates the amplitude of nuclear import receptors-dependent functions in different contexts and adds complexity in considering their therapeutic implications.

Keywords: ciliogenesis; importin beta family; mitotic spindle; neurodegenerative diseases; nuclear transport; nucleoporins; protein aggregates; ubiquitin/proteasome system

DOI: https://doi.org/10.3389/fcell.2022.1041938

Biol Direct. 2022 Dec 02. 17(1): 38

p53 regulates expression of nuclear envelope components in cancer cells.

Emanuele Panatta, Alessio Butera, Ivana Celardo, Marcel Leist, Gerry Melino, Ivano Amelio.

Nuclear organisation and architecture are essential for the maintenance of genomic integrity as well as for the epigenetic regulations and gene expression. Disruption of lamin B1, major structural and functional member of the nuclear lamina, is observed in human laminopathies and in sporadic cancers, and leads to chromosomal rearrangements and alterations of gene expression. The tumour suppressor p53 has been shown to direct specific transcriptional programmes by regulating lamin A/C, however its relationship with lamin B1 has remained elusive. Here, we show that loss of p53 correlates with increased expression of members belonging to the nuclear pore complex and nuclear lamina and directly regulates transcription of lamin B1. We show that the genomic loci of a fraction of p53-dependent genes physically interact with lamin B1 and Nup210. This observation provides a possible mechanistic explanation for the p53-depedent changes of chromatin accessibility, with the consequent influence of expression and rearrangement of these genomic sites in pancreatic cancer. Overall, these data suggest a potential functional and biochemical regulatory network connecting p53 and nuclear architecture.

DOI: https://doi.org/10.1186/s13062-022-00349-3

Biophys J. 2022 Nov 29. pii: S0006-3495(22)03861-9. [Epub ahead of print]

Predicting YAP/TAZ Nuclear Translocation in Response to ECM Mechanosensing.

Bo Cheng, Moxiao Li, Wanting Wan, Hui Guo, Guy M Genin, Min Lin, Feng Xu.

Cells translate mechanical cues from the extracellular matrix (ECM) into signaling that can affect the nucleus. One pathway by which such nuclear mechanotransduction occurs is a signaling axis that begins with integrin-ECM bonds and continues through a cascade of chemical reactions and structural changes that lead to nuclear translocation of the YAP/TAZ which is independent of hippo pathway. This signaling axis is self-reinforcing, with stiff ECM promoting integrin binding and thus facilitating polymerization and tension in the cytoskeletal contractile apparatus, which can compress nuclei, open nuclear pore channels, and enhance nuclear accumulation of YAP/TAZ. We previously developed a computational model of this mechanosensing axis for the linear elastic ECM by assuming that there is a linear relationship between the nucleocytoplasmic ratio of YAP/TAZ and nuclear flattening. Here, we extended our previous model to more general ECM behaviors (e.g., viscosity, viscoelasticity and viscoplasticity) and included more details about YAP/TAZ translocation dynamics based on nuclear deformation. This model was predictive of diverse mechanosensing responses in a broad range of cells. Results support the hypothesis that this diverse range of mechanosensing phenomena across many cell types arises from a simple, unified set of mechanosensing pathways.

DOI: https://doi.org/10.1016/j.bpj.2022.11.2943