Nesprins: from the nuclear envelope and beyond

The LINC complex is a multifunctional protein complex that is involved in various processes at the nuclear envelope, such as nuclear migration, mechanotransduction and chromatin tethering in the meiotic phase. However, it remains unknown how these functions are regulated in different cell contexts. An inner nuclear membrane component of the LINC complex, SUN1, is ubiquitously expressed. The human SUN1 gene produces over 10 variants by alternative splicing. Although functions of SUN1 are relatively well characterized, functional differences among SUN1 splice variants are poorly characterized. LINC complex components are associated with a wide range of human diseases; therefore, it is important to understand the functional diversity among SUN1 splice variants. Here, we identified a novel human SUN1 splice variant, SUN1_888. overexpression of the SUN1 splice variants, SUN1_888 or SUN1_785, but not the predominant isoform, SUN1_916, activated directional cell migration. Knockdown of SUN1_888 suppressed cell migration; in contrast depletion of SUN1_916 activated cell migration. In addition, all of investigated SUN1 splicing variants rescued cell migration in SUN1 knock out cell. These results indicate that redundant and non-redundant functions of SUN1 splice variant in directional cell migration and suggest that variable LINC complexes with distinct task may exit. Furthermore, in contrast to previous studies, we showed association between SUN1 and B-type lamins. Interestingly, B-type lamin preferentially interacts with SUN1 but not SUN2. These results suggest that tissue-specific SUN1 variants variably interact with nucleoplasmic partners and allow variable assembly of LINC complexes that can be assigned to distinct tasks.

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“…[1][2][3][4] Mammalian SUN proteins are encoded by at least 5 genes, SUN1»5. SUN1 and SUN2 are widely expressed in mammalian somatic cells.…”

Section: Introductionmentioning

confidence: 99%

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

Nishioka

Imaizumi

Imada

et al. 2016

Nucleus

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“…This indicates that they are highly versatile components, rather than a plain linear linker between nuclear membrane and cytoskeletal elements. [12][13][14] It remains unclear if invertebrates like Drosophila possess intranuclear Nesprin isoforms, too, and if so, how they enter the nuclear envelope and whether they directly interact with the inner nuclear membrane (INM) and chromatin.…”

Section: Nesprins Are Required For Tensional Homeostasis and Force Trmentioning

confidence: 99%

Composite biopolymer scaffolds shape muscle nucleus: Insights and perspectives fromDrosophila

Wang

Volk

2015

BioArchitecture

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Contractile muscle fibers produce enormous intrinsic forces during contraction/relaxation waves. These forces are directly applied to their cytoplasmic organelles including mitochondria, sarcoplasmic reticulum, and multiple nuclei. Data from our analysis of Drosophila larval somatic muscle fibers suggest that an intricate network of organized microtubules (MT) intermingled with Spectrin-Repeat-Containing Proteins (SRCPs) are major structural elements that protect muscle organelles and maintain their structure and position during muscle contraction. Whereas the perinuclear MT network provides structural rigidity to the myonucleus, the SRCPs Nesprin and Spectraplakin form semiflexible filamentous biopolymer networks, providing nuclei with the elasticity required to resist the contractile cytoplasmic forces produced by the muscle. Spectrin repeats are domains found in numerous structural proteins, which are able to unfold under tension and are subject to mechanical stresses in the cell. This unique composite scaffold combines rigidity and resilience in order to neutralize the oscillating cellular forces occurring during muscle contraction/ relaxation waves and thereby protect myonuclei. We suggest that the elastic properties of SRCPs are critical for nuclear protection and proper function in muscle fibers.

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“…We documented that nesprin-1 and -2 give rise to a vast array of tissue specific isoforms of different sizes [14] including i) isoforms lacking the KASH domain (14 for nesprin-1 and 5 for nesprin-2); ii) isoforms lacking the CHDs (16 for nesprin-1 and 12 for nesprin-2) [16], and iii) SR-only isoforms for nesprin-1 [17]. The isoform repertoire reflects emerging new functions of nesprins beyond the NE.…”

Section: Introductionmentioning

confidence: 99%

“…The isoform repertoire reflects emerging new functions of nesprins beyond the NE. The isoforms are generated by alternate promotor usage, pre-mRNA 3' end processing, and alternative splicing (including or excluding cassette exons) [14,16,18]. For example, nesprin-2α1 and -2α2 variants are generated via different initiation within 5' untranslated region (UTR) ( Figure 1A) [1,7].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore the identification and verification of novel transcripts is essential for a complete understanding of nesprin biology [1,14,7]. In this chapter we discuss the techniques we have used including: i) 5' and 3' Rapid Amplification of cDNA Ends (RACE) for identifying cDNA ends that represent novel 5' and/or 3' UTRs, in combination with the EST database analysis, in which there is a vast collection of partial sequences of cDNA clones available; ii) RT-PCR from multi-tissue cDNAs using alternatively combined 5' and 3' UTRs for identifying and validating putative isoforms [1,16,7,23]. …”

Section: Introductionmentioning

confidence: 99%

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Identification and Validation of Putative Nesprin Variants

Autore

Shanahan

Zhang

2016

Methods in Molecular Biology

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SummaryNesprins are a family of multi-isomeric scaffolding proteins that were originally identified at the nuclear envelope (NE), where they bind to lamin A/C, emerin and SUN-domain containing proteins, to form the LInker of Nucleoskeleton-andCytoskeleton (LINC) complex that connects the NE to the actin cytoskeleton. However, nesprin genes also give rise to a variety of tissue specific variants of different sizes with potential roles beyond the NE. These variants are generated through alternative initiation, termination and splicing, which makes nesprin biology very complex to study due to the difficulty in generating specific antibodies and/or short interfering RNAs (siRNA) to particular isoforms. In order to distinguish genuine nesprin variants and eliminate confusion with degradation products of larger nesprin isoforms, in this chapter we discuss methods including 5' and 3' Rapid Amplification of cDNA Ends (RACE) and RT-PCR in combination with EST database searching, for identifying and validating putative nesprin isoforms. This information is essential to allow a better understanding of nesprin functions in different cell types.

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Nesprins: from the nuclear envelope and beyond

Cited by 172 publications

References 88 publications

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

SUN1 splice variants, SUN1_888, SUN1_785, and predominant SUN1_916, variably function in directional cell migration

Composite biopolymer scaffolds shape muscle nucleus: Insights and perspectives fromDrosophila

Identification and Validation of Putative Nesprin Variants

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