bims-nucpor 2022-04-24 papers

Issue of 2022‒04‒24
three papers selected by
Sara Mingu
Johannes Gutenberg University

Cells. 2022 Apr 07. pii: 1259. [Epub ahead of print]11(8):

NUP133 Controls Nuclear Pore Assembly, Transcriptome Composition, and Cytoskeleton Regulation in Podocytes.

Manuel Rogg, Jasmin I Maier, Markus Ehle, Alena Sammarco, Oliver Schilling, Martin Werner, Christoph Schell.

Steroid-resistant nephrotic syndrome (SRNS) frequently leads to end-stage renal disease, ultimately requiring kidney replacement therapies. SRNS is often caused by hereditary monogenic mutations, specifically affecting specialized epithelial cells (podocytes) of the glomerular filtration barrier. Mutations in several components of the nuclear pore complex, including NUP133 and NUP107, have been recently identified to cause hereditary SRNS. However, underlying pathomechanisms, eliciting podocyte-specific manifestations of these nucleoporopathies, remained largely elusive. Here, we generated an in vitro model of NUP133-linked nucleoporopathies using CRISPR/Cas9-mediated genome editing in human podocytes. Transcriptome, nuclear pore assembly, and cytoskeleton regulation of NUP133 loss-of-function, mutant, and wild-type podocytes were analyzed. Loss of NUP133 translated into a disruption of the nuclear pore, alterations of the podocyte-specific transcriptome, and impaired cellular protrusion generation. Surprisingly, comparative analysis of the described SRNS-related NUP133 mutations revealed only mild defects. Am impaired protein interaction in the Y-complex and decrease of NUP133 protein levels might be the primary and unifying consequence of mutant variants, leading to a partial loss-of-function phenotype and disease manifestation in susceptible cell types, such as podocytes.

Keywords: NUP133; SRNS; nuclear pore complex; nucleoporin; nucleoporopathy; podocyte; podocytopathy

DOI: https://doi.org/10.3390/cells11081259

Mol Microbiol. 2022 Apr 17.

Adenovirus Entry - Stability, Uncoating and Nuclear Import.

Urs F Greber, Maarit Suomalainen.

Adenoviruses (AdV) are wide-spread in vertebrates. They infect the respiratory and gastrointestinal tracts, the eyes, heart, liver and kidney, and are lethal to immunosuppressed people. Mastadenoviruses infecting mammals comprise several hundred different types, and many specifically infect humans. Human adenoviruses are the most widely used vectors in clinical applications, including cancer treatment and COVID-19 vaccination. AdV vectors are physically and genetically stable, and generally safe in humans. The particles have an icosahedral coat and a nucleo-protein core with a DNA genome. We describe a coherent concept of AdV entry, and highlight recent advances in cytoplasmic transport, uncoating and nuclear import of the viral DNA, including microtubule motors. We highlight a 'linchpin' function of the virion protein V ensuring cytoplasmic particle stability, which is relaxed at the nuclear pore complex by cues from the E3-ubiquitin ligase Mind bomb 1 (MIB1) and the proteasome triggering disruption. Capsid disruption by kinesin motor proteins and microtubules then exposes the linchpin and renders protein V a target for MIB1 ubiquitination, which dissociates V from viral DNA and enhances DNA nuclear import. These advances uncover surprising mechanisms controlling capsid stability and premature uncoating, and provide insight into nuclear transport of nucleic acids.

Keywords: DNA nuclear transport; Mind bomb 1 (MIB1) E3 ubiquitin ligase; Virus entry and disassembly; nuclear pore complex (NPC); ubiquitin proteasome system

DOI: https://doi.org/10.1111/mmi.14909

J Cell Biol. 2022 Jun 06. pii: e202201094. [Epub ahead of print]221(6):

Tumor suppressor BAP1 nuclear import is governed by transportin-1.

Tzu-Jing Yang, Tian-Neng Li, Rih-Sheng Huang, Max Yu-Chen Pan, Shu-Yu Lin, Steven Lin, Kuen-Phon Wu, Lily Hui-Ching Wang, Shang-Te Danny Hsu.

Subcellular localization of the deubiquitinating enzyme BAP1 is deterministic for its tumor suppressor activity. While the monoubiquitination of BAP1 by an atypical E2/E3-conjugated enzyme UBE2O and BAP1 auto-deubiquitination are known to regulate its nuclear localization, the molecular mechanism by which BAP1 is imported into the nucleus has remained elusive. Here, we demonstrated that transportin-1 (TNPO1, also known as Karyopherin β2 or Kapβ2) targets an atypical C-terminal proline-tyrosine nuclear localization signal (PY-NLS) motif of BAP1 and serves as the primary nuclear transporter of BAP1 to achieve its nuclear import. TNPO1 binding dissociates dimeric BAP1 and sequesters the monoubiquitination sites flanking the PY-NLS of BAP1 to counteract the function of UBE2O that retains BAP1 in the cytosol. Our findings shed light on how TNPO1 regulates the nuclear import, self-association, and monoubiquitination of BAP1 pertinent to oncogenesis.

DOI: https://doi.org/10.1083/jcb.202201094