Recognition of the TDP-43 nuclear localization signal by importin α1/β

Doll, Steven G.; Meshkin, Hamed; Bryer, Alexander J.; Li, Fenglin; Ko, Ying‐Hui; Lokareddy, Ravi K.; Gillilan, Richard E.; Gupta, Kushol; Perilla, Juan R.; Cingolani, Gino

doi:10.1016/j.celrep.2022.111007

Cited by 40 publications

(52 citation statements)

References 95 publications

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“…The sequence of the TDP-43 NLS contains two patches of basic residues that allow binding of both the major and minor NLS sites on Imp α1 (Figure 1A). Doll et al [7] have shown that the TDP-43 NLS does adhere to the bipartite binding mechanism, with the N-terminal 82-KRK-84 sequence located at the minor site in the structure, while the C-terminal 95-KVKR-98 sequence is at the major site. This is similar to that of other bi-partite NLSs, including that of nucleoplasmin.…”

Section: Unique Properties Of Tdp-43 Bipartite Nlsmentioning

confidence: 99%

Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?

Doll

Cingolani

2022

BioEssays

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The transactivation response‐DNA binding protein of 43 kDa (TDP‐43) is an aggregation‐prone nucleic acid‐binding protein linked to the etiology of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD). These conditions feature the accumulation of insoluble TDP‐43 aggregates in the neuronal cytoplasm that lead to cell death. The dynamics between cytoplasmic and nuclear TDP‐43 are altered in the disease state where TDP‐43 mislocalizes to the cytoplasm, disrupting Nuclear Pore Complexes (NPCs), and ultimately forming large fibrils stabilized by the C‐terminal prion‐like domain. Here, we review three emerging and poorly understood aspects of TDP‐43 biology linked to its aggregation. First, how post‐translational modifications in the proximity of TDP‐43 N‐terminal domain (NTD) promote aggregation. Second, how TDP‐43 engages FG‐nucleoporins in the NPC, disrupting the pore permeability and function. Third, how the importin α/β heterodimer prevents TDP‐43 aggregation, serving both as a nuclear import transporter and a cytoplasmic chaperone.

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Section: Unique Properties Of Tdp-43 Bipartite Nlsmentioning

confidence: 99%

Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?

Doll

Cingolani

2022

BioEssays

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“…S4G ). TDP-43 contains a bipartite nuclear localization signal (NLS) domain (81-87 amino acids and 94-100 amino acids) ( 34 ). The ΔN mutant of TDP-43 localized to the nucleus despite of lacking a part of the domain ( fig.…”

Section: Resultsmentioning

confidence: 99%

TDP-43 safeguards the embryo genome from L1 retrotransposition

Murano

Kitano

et al. 2022

Preprint

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Transposable elements (TEs) are genomic parasites that propagate within the host genome and introduce mutations. Long interspersed nuclear element-1 (LINE-1 or L1) is the major TE class, which occupies nearly 20% of the mouse genome. L1 is highly active in mammalian preimplantation embryos, posing a major threat to genome integrity, but the mechanism of stage-specific protection against L1 retrotransposition is unknown. Here, we show that TAR DNA binding protein 43 (TDP-43), mutations in which constitute a major risk factor for amyotrophic lateral sclerosis (ALS), inhibits L1 retrotransposition in mouse embryonic stem cells (mESCs) and preimplantation embryos. Knock-down of TDP-43 resulted in massive genomic L1 expansion and impaired cell growth in preimplantation embryos and ESCs. Functional analysis demonstrated that TDP-43 interacts with L1 open reading frame 1 protein (L1 ORF1p) to mediate genomic protection, and loss of this interaction led to de-repression of L1 retrotransposition. Our results identify TDP-43 as a guardian of the embryonic genome.

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“…TDP-43 is also prone to form aggregates that can be solubilised by importin alpha/importin beta-1 binding to its bipartite NLS ( Doll et al, 2022 ). TDP-43 mutations, also found in a proportion of ALS and FTD cases, yield cytoplasmic aggregates that mislocalise nucleo-cytoplasmic regulators, hence amplifying nuclear transport defects ( Chou et al, 2018 ; Gasset-Rosa et al, 2019 ).…”

Section: Nuclear Import Receptors Prevent Aberrant Phase Separation O...mentioning

confidence: 99%

“…Expression of dominantnegative importin beta-1 phenocopies the effects of CRB3-CLPI knockdown (loss of cilia, centrosomal and spindle abnormalities). NLS Importin alpha/beta-1 binding to NLS of TDP-43 disrupts its dimerisation interface and prevents the formation of aggregates Guo et al (2018),Doll et al (2022). (Continued on following page)Frontiers in Cell and Developmental Biology frontiersin.org…”

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confidence: 99%

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

Damizia

Altieri²,

Lavia³

2022

Front. Cell Dev. Biol.

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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.

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Recognition of the TDP-43 nuclear localization signal by importin α1/β

Cited by 40 publications

References 95 publications

Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?

Importin α/β and the tug of war to keep TDP‐43 in solution: quo vadis?

TDP-43 safeguards the embryo genome from L1 retrotransposition

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

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