bims-nucpor 2021-12-19 papers

Issue of 2021–12–19
five papers selected by
Sara Mingu, Johannes Gutenberg University

Cancer Discov. 2021 Dec 13. pii: candisc.0674.2021. [Epub ahead of print]

Phase Separation mediates NUP98 Fusion Oncoprotein Leukemic Transformation.

NUP98 fusion oncoproteins (FOs) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form, and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0674

Life Sci Alliance. 2022 Mar;pii: e202101216. [Epub ahead of print]5(3):

Loss of Nup210 results in muscle repair delays and age-associated alterations in muscle integrity.

Stephen Sakuma, Ethan Ys Zhu, Marcela Raices, Pan Zhang, Rabi Murad, Maximiliano A D'Angelo.

Nuclear pore complexes, the channels connecting the nucleus with the cytoplasm, are built by multiple copies of ∼30 proteins called nucleoporins. Recent evidence has exposed that nucleoporins can play cell type-specific functions. Despite novel discoveries into the cellular functions of nucleoporins, their role in the regulation of mammalian tissue physiology remains mostly unexplored because of a limited number of nucleoporin mouse models. Here we show that ablation of Nup210/Gp210, a nucleoporin previously identified to play a role in myoblast differentiation and Zebrafish muscle maturation, is dispensable for skeletal muscle formation and growth in mice. We found that although primary satellite cells from Nup210 knockout mice can differentiate, these animals show delayed muscle repair after injury. Moreover, Nup210 knockout mice display an increased percentage of centrally nucleated fibers and abnormal fiber type distribution as they age. Muscle function experiments also exposed that Nup210 is required for muscle endurance during voluntary running. Our findings indicate that in mammals, Nup210 is important for the maintenance of skeletal muscle integrity and for proper muscle function providing novel insights into the in vivo roles of nuclear pore complex components.

DOI: https://doi.org/10.26508/lsa.202101216

Mol Cell. 2021 Dec 16. pii: S1097-2765(21)01031-5. [Epub ahead of print]81(24): 4962-4963

Nuclear pore complexes feel the strain.

C Patrick Lusk, Megan C King.

A cryo-electron tomography structure of the human nuclear pore complex captured in cellulo by Schuller, Wojtynek et al. reveals that nuclear envelope tension expands the central transport channel and imposes asymmetry in the pore membrane.

DOI: https://doi.org/10.1016/j.molcel.2021.11.029

Nat Commun. 2021 Dec 13. 12(1): 7216

Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.

Ruhul Amin, Anjali Shukla, Jacqueline Jufen Zhu, Sohyoung Kim, Ping Wang, Simon Zhongyuan Tian, Andy D Tran, Debasish Paul, Steven D Cappell, Sandra Burkett, Huaitian Liu, Maxwell P Lee, Michael J Kruhlak, Jennifer E Dwyer, R Mark Simpson, Gordon L Hager, Yijun Ruan, Kent W Hunter.

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis.

DOI: https://doi.org/10.1038/s41467-021-27451-w

PLoS Pathog. 2021 Dec;17(12): e1010132

Infection-induced chromatin modifications facilitate translocation of herpes simplex virus capsids to the inner nuclear membrane.

Vesa Aho, Sami Salminen, Salla Mattola, Alka Gupta, Felix Flomm, Beate Sodeik, Jens B Bosse, Maija Vihinen-Ranta.

Herpes simplex virus capsids are assembled and packaged in the nucleus and move by diffusion through the nucleoplasm to the nuclear envelope for egress. Analyzing their motion provides conclusions not only on capsid transport but also on the properties of the nuclear environment during infection. We utilized live-cell imaging and single-particle tracking to characterize capsid motion relative to the host chromatin. The data indicate that as the chromatin was marginalized toward the nuclear envelope it presented a restrictive barrier to the capsids. However, later in infection this barrier became more permissive and the probability of capsids to enter the chromatin increased. Thus, although chromatin marginalization initially restricted capsid transport to the nuclear envelope, a structural reorganization of the chromatin counteracted that to promote capsid transport later. Analyses of capsid motion revealed that it was subdiffusive, and that the diffusion coefficients were lower in the chromatin than in regions lacking chromatin. In addition, the diffusion coefficient in both regions increased during infection. Throughout the infection, the capsids were never enriched at the nuclear envelope, which suggests that instead of nuclear export the transport through the chromatin is the rate-limiting step for the nuclear egress of capsids. This provides motivation for further studies by validating the importance of intranuclear transport to the life cycle of HSV-1.

DOI: https://doi.org/10.1371/journal.ppat.1010132