bims-nucpor 2022-05-08 papers

Issue of 2022–05–08
three papers selected by
Sara Mingu, Johannes Gutenberg University

RNA Biol. 2022 Jan;19(1): 650-661

Trafficking and/or division: Distinct roles of nucleoporins based on their location within the nuclear pore complex.

Eva Hegedűsová, Veronika Maršalová, Sneha Kulkarni, Zdeněk Paris.

The nuclear pore complex (NPC) facilitates the trafficking of proteins and RNA between the nucleus and cytoplasm. The role of nucleoporins (Nups) in transport in the context of the NPC is well established, yet their function in tRNA export has not been fully explored. We selected several nucleoporins from different parts of the NPC to investigate their potential role in tRNA trafficking in Trypanosoma brucei. We show that while all of the nucleoporins studied are essential for cell viability, only TbNup62 and TbNup53a function in tRNA export. In contrast to homologs in yeast TbNup144 and TbNup158, which are part of the inner and outer ring of the NPC, have no role in nuclear tRNA trafficking. Instead, TbNup144 plays a critical role in nuclear division, highlighting the role of nucleoporins beyond nucleocytoplasmic transport. These results suggest that the location of nucleoporins within the NPC is crucial to maintaining various cellular processes.

Keywords: FG-Nups; NPC; Trypanosoma brucei; nuclear division; nucleoporins; tRNA trafficking

DOI: https://doi.org/10.1080/15476286.2022.2067711

Biochemistry (Mosc). 2022 Jan;87(Suppl 1): S178-S70

Targeting XPO1-Dependent Nuclear Export in Cancer.

Ekaterina Kim, Daria A Mordovkina, Alexey Sorokin.

Nucleocytoplasmic transport of macromolecules is tightly regulated in eukaryotic cells. XPO1 is a transport factor responsible for the nuclear export of several hundred protein and RNA substrates. Elevated levels of XPO1 and recurrent mutations have been reported in multiple cancers and linked to advanced disease stage and poor survival. In recent years, several novel small-molecule inhibitors of XPO1 were developed and extensively tested in preclinical cancer models and eventually in clinical trials. In this brief review, we summarize the functions of XPO1, its role in cancer, and the latest results of clinical trials of XPO1 inhibitors.

Keywords: SINE; XPO1; cancer; nuclear export; selinexor

DOI: https://doi.org/10.1134/S0006297922140140

Autophagy. 2022 May 04. 1-26

Nucleoporin POM121 signals TFEB-mediated autophagy via activation of SIGMAR1/sigma-1 receptor chaperone by pridopidine.

Shao-Ming Wang, Hsiang-En Wu, Yuko Yasui, Michal Geva, Michael Hayden, Tangui Maurice, Mauro Cozzolino, Tsung-Ping Su.

Macroautophagy/autophagy is an essential process for cellular survival and is implicated in many diseases. A critical step in autophagy is the transport of the transcription factor TFEB from the cytosol into the nucleus, through the nuclear pore (NP) by KPNB1/importinβ1. In the C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal lobar degeneration (ALS-FTD), the hexanucleotide (G4C2)RNA expansion (HRE) disrupts the nucleocytoplasmic transport of TFEB, compromising autophagy. Here we show that a molecular chaperone, the SIGMAR1/Sigma-1 receptor (sigma non-opioid intracellular receptor 1), facilitates TFEB transport into the nucleus by chaperoning the NP protein (i.e., nucleoporin) POM121 which recruits KPNB1. In NSC34 cells, HRE reduces TFEB transport by interfering with the association between SIGMAR1 and POM121, resulting in reduced nuclear levels of TFEB, KPNB1, and the autophagy marker LC3-II. Overexpression of SIGMAR1 or POM121, or treatment with the highly selective and potent SIGMAR1 agonist pridopidine, currently in phase 2/3 clinical trials for ALS and Huntington disease, rescues all of these deficits. Our results implicate nucleoporin POM121 not merely as a structural nucleoporin, but also as a chaperone-operated signaling molecule enabling TFEB-mediated autophagy. Our data suggest the use of SIGMAR1 agonists, such as pridopidine, for therapeutic development of diseases in which autophagy is impaired.Abbreviations: ALS-FTD, amyotrophic lateral sclerosis-frontotemporal dementiaC9ALS-FTD, C9orf72 subtype of amyotrophic lateral sclerosis-frontotemporal dementiaCS, citrate synthaseER, endoplasmic reticulumGSS, glutathione synthetaseHRE, hexanucleotide repeat expansionHSPA5/BiP, heat shock protein 5LAMP1, lysosomal-associated membrane protein 1MAM, mitochondria-associated endoplasmic reticulum membraneMAP1LC3/LC3, microtubule-associated protein 1 light chain 3NP, nuclear poreNSC34, mouse motor neuron-like hybrid cell lineNUPs, nucleoporinsPOM121, nuclear pore membrane protein 121SIGMAR1/Sigma-1R, sigma non-opioid intracellular receptor 1TFEB, transcription factor EBTMEM97/Sigma-2R, transmembrane protein 97.

Keywords: ALS/FTD; KPNB1/importinβ1; SIGMAR1; TFEB; c9orf72; chaperone; nucleocytoplasmic transport; nucleoporin POM121; pridopidine; sigma-1 receptor

DOI: https://doi.org/10.1080/15548627.2022.2063003