bims-nucpor 2022-10-30 papers

Issue of 2022–10–30
four papers selected by
Sara Mingu, Johannes Gutenberg University

Nat Cell Biol. 2022 Oct 27.

The chaperone DNAJB6 surveils FG-nucleoporins and is required for interphase nuclear pore complex biogenesis.

E F Elsiena Kuiper, Paola Gallardo, Tessa Bergsma, Muriel Mari, Maiara Kolbe Musskopf, Jeroen Kuipers, Ben N G Giepmans, Anton Steen, Harm H Kampinga, Liesbeth M Veenhoff, Steven Bergink.

Biogenesis of nuclear pore complexes (NPCs) includes the formation of the permeability barrier composed of phenylalanine-glycine-rich nucleoporins (FG-Nups) that regulate the selective passage of biomolecules across the nuclear envelope. The FG-Nups are intrinsically disordered and prone to liquid-liquid phase separation and aggregation when isolated. How FG-Nups are protected from making inappropriate interactions during NPC biogenesis is not fully understood. Here we find that DNAJB6, a molecular chaperone of the heat shock protein network, forms foci in close proximity to NPCs. The number of these foci decreases upon removal of proteins involved in the early steps of interphase NPC biogenesis. Conversely, when this process is stalled in the last steps, the number of DNAJB6-containing foci increases and these foci are identified as herniations at the nuclear envelope. Immunoelectron tomography shows that DNAJB6 localizes inside the lumen of the herniations arising at NPC biogenesis intermediates. Loss of DNAJB6 results in the accumulation of cytosolic annulate lamellae, which are structures containing partly assembled NPCs, a feature associated with disturbances in NPC biogenesis. We find that DNAJB6 binds to FG-Nups and can prevent the aggregation of the FG region of several FG-Nups in cells and in vitro. Together, our data show that the molecular chaperone DNAJB6 provides quality control during NPC biogenesis and is involved in the surveillance of native intrinsically disordered FG-Nups.

DOI: https://doi.org/10.1038/s41556-022-01010-x

Dev Cell. 2022 Oct 24. pii: S1534-5807(22)00719-5. [Epub ahead of print]57(20): 2397-2411.e9

Changes in nuclear pore numbers control nuclear import and stress response of mouse hearts.

Lu Han, Jocelyn D Mich-Basso, Yao Li, Niyatie Ammanamanchi, Jianquan Xu, Anita P Bargaje, Honghai Liu, Liwen Wu, Jong-Hyeon Jeong, Jonathan Franks, Donna B Stolz, Yijen L Wu, Dhivyaa Rajasundaram, Yang Liu, Bernhard Kühn.

Nuclear pores are essential for nuclear-cytoplasmic transport. Whether and how cells change nuclear pores to alter nuclear transport and cellular function is unknown. Here, we show that rat heart muscle cells (cardiomyocytes) undergo a 63% decrease in nuclear pore numbers during maturation, and this changes their responses to extracellular signals. The maturation-associated decline in nuclear pore numbers is associated with lower nuclear import of signaling proteins such as mitogen-activated protein kinase (MAPK). Experimental reduction of nuclear pore numbers decreased nuclear import of signaling proteins, resulting in decreased expression of immediate-early genes. In a mouse model of high blood pressure, reduction of nuclear pore numbers improved adverse heart remodeling and reduced progression to lethal heart failure. The decrease in nuclear pore numbers in cardiomyocyte maturation and resulting functional changes demonstrate how terminally differentiated cells permanently alter their handling of information flux across the nuclear envelope and, with that, their behavior.

Keywords: Lamin B2; MAP kinase; NFκB; Nup155; cardiac hypertrophy; cardiac remodeling; cardiomyocyte; nuclear pore; nuclear transport

DOI: https://doi.org/10.1016/j.devcel.2022.09.017

Nat Cell Biol. 2022 Oct 27.

Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities.

Sarah M Prophet, Anthony J Rampello, Robert F Niescier, Juliana E Gentile, Sunanda Mallik, Anthony J Koleske, Christian Schlieker.

DYT1 dystonia is a debilitating neurological movement disorder arising from mutation in the AAA+ ATPase TorsinA. The hallmark of Torsin dysfunction is nuclear envelope blebbing resulting from defects in nuclear pore complex biogenesis. Whether blebs actively contribute to disease manifestation is unknown. We report that FG-nucleoporins in the bleb lumen form aberrant condensates and contribute to DYT1 dystonia by provoking two proteotoxic insults. Short-lived ubiquitylated proteins that are normally rapidly degraded partition into the bleb lumen and become stabilized. In addition, blebs selectively sequester a specific HSP40-HSP70 chaperone network that is modulated by the bleb component MLF2. MLF2 suppresses the ectopic accumulation of FG-nucleoporins and modulates the selective properties and size of condensates in vitro. Our study identifies dual mechanisms of proteotoxicity in the context of condensate formation and establishes FG-nucleoporin-directed activities for a nuclear chaperone network.

DOI: https://doi.org/10.1038/s41556-022-01001-y

Elife. 2022 Oct 27. pii: e70495. [Epub ahead of print]11

Kap-β2/Transportin mediates β-catenin nuclear transport in Wnt signaling.

Woong Y Hwang, Valentyna Kostiuk, Delfina P González, C Patrick Lusk, Mustafa Khokha.

Wnt signaling is essential for many aspects of embryonic development including the formation of the primary embryonic axis. In addition, excessive Wnt signaling drives multiple diseases including cancer highlighting its importance for disease pathogenesis. β-catenin is a key effector in this pathway that translocates into the nucleus and activates Wnt responsive genes. However, due to our lack of understanding of β-catenin nuclear transport, therapeutic modulation of Wnt signaling has been challenging. Here, we took an unconventional approach to address this long-standing question by exploiting a heterologous model system, the budding yeast Saccharomyces cerevisiae, which contains a conserved nuclear transport machinery. In contrast to prior work, we demonstrate that β-catenin accumulates in the nucleus in a Ran dependent manner, suggesting the use of a nuclear transport receptor (NTR). Indeed, a systematic and conditional inhibition of NTRs revealed that only Kap104, the orthologue of Kap-β2/Transportin-1 (TNPO1), was required for β-catenin nuclear import. We further demonstrate direct binding between TNPO1 and β-catenin that is mediated by a conserved PY-NLS. Finally, using Xenopus secondary axis and TCF/LEF reporter assays, we demonstrate that our results in yeast can be directly translated to vertebrates. By elucidating the NLS in β-catenin and its cognate NTR, our study suggests new therapeutic targets for a host of human diseases caused by excessive Wnt signaling. Indeed, we demonstrate that a small chimeric peptide designed to target TNPO1 can reduce Wnt signaling as a first step towards therapeutics.

Keywords: S. cerevisiae; cell biology; developmental biology; xenopus

DOI: https://doi.org/10.7554/eLife.70495