The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies’. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases.
Identification of protein-protein interactions is a major goal of biological research. Despite technical advances over the last two decades, important but still largely unsolved challenges include the high-throughput detection of interactions directly from primary tissue and the identification of interactors of insoluble proteins that form higher-order structures. We have developed a novel, proximity-based labeling approach that uses antibodies to guide biotin deposition onto adjacent proteins in fixed cells and primary tissues. We showed our method to be specific and sensitive by labeling a mitochondrial matrix protein. Next, we used this method to profile the dynamic interactome of lamin A/C in multiple cell and tissue types under various treatment conditions. The ability to detect proximal proteins and putative interactors in intact tissues, and to quantify changes caused by different conditions or in the presence of disease mutations, can provide a new window into cell biology and disease pathogenesis.
Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.Caenorhabditis elegans | metabolism | mTOR pathway | TORC1 D ietary restriction (DR), limiting food consumption below ad libitum to levels that do not cause malnutrition, is a highly conserved metabolic intervention. Different DR regimes extend the lifespan of most tested animal species (1). Moreover, DR regimens have been found to reduce the risk of diabetes in monkeys and to positively change metabolic health biomarkers in humans (2). Lifelong DR causes reduced body size, lower fat levels, and a smaller brood size (3-6). Although the pathways by which DR extends lifespan have been thoroughly investigated, less is known about the causes of reduced body size and fat content.Multiple DR regimens have been developed for Caenorhabditis elegans (7). Surprisingly, the different DR regimens vary in the genes essential for lifespan extension (7). For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate. Unlike bacterial dilution, this model was shown to be independent of both daf-16 and aak-2, at least with respect to lifespan (7).The mechanistic target of rapamycin (mTOR) pathway is a key regulator of multiple processes, including transcription and translation, protein and lipid synthesis, cell growth and size, and cellular metabolism (9). It contains two main protein complexes, mTOR complex 1 (TORC1) and complex 2 (TORC2) (10). TOR...
Lamins are nuclear intermediate filament proteins. They provide mechanical stability, organize chromatin and regulate transcription, replication, nuclear assembly and nuclear positioning. Recent studies provide new insights into the role of lamins in development, differentiation and tissue response to mechanical, reactive oxygen species and thermal stresses. These studies also propose the existence of separate filament networks for A-and B-type lamins and identify new roles for the different networks. Furthermore, they show changes in lamin composition in different cell types, propose explanations for the more than 14 distinct human diseases caused by lamin A and lamin C mutations and propose a role for lamin B1 in these diseases. Keywords: development; lamin; nuclear envelope; nuclear lamina; stress EMBO reports (2012) 13, 1070-1078; published online 13 November 2012; doi:10.1038/embor.2012 See the Glossary for abbreviations used in this article.Lamins are evolutionarily conserved nuclear intermediate filament proteins. They are restricted to the animal kingdom and are the main constituents of the nuclear lamina, which is a meshwork of lamins at the nuclear periphery and their associated proteins. Similarly to most intermediate filament proteins, lamins have a conserved α-helical coiled-coil rod domain flanked by variable amino-terminal head and carboxy-terminal tail domains [1]. The tail domain of lamins contains an immunoglobulin-like fold motif and a nuclear localization signal. Except for lamin C, all lamins are translated as prelamins with a C-terminal CaaX motif, which undergoes farnesylation. In Xenopus oocytes, lamins form filaments of about 10 nm in diameter, which are arranged in a regular, parallel pattern [2,3]. The basic building-block for higher-order lamin assembly is the lamin dimer. The first step in this assembly involves head-to-tail polymerization of the lamin dimers [4]. These polymers associate laterally in an antiparallel fashion to form the protofilament, and then between three and four protofilaments form the lamin filament [5]. However, the structure of lamin in somatic cells in vivo still needs to be determined. There is an uneven distribution of the lamin subtypes during development and throughout human tissues [6][7][8]. All somatic cell types, including embryonic stem cells (ESCs), express lamin B1 and/or lamin B2 (B-type lamins), which are encoded by LMNB1 and LMNB2 genes, respectively. Lamin A and lamin C are expressed from the LMNA gene through alternative splicing (A-type lamins), and differ from each other in their C-terminal tail domain. They are developmentally regulated and are not essential for somatic cell survival. Lamin A, lamin B1 and lamin B2 originate from prelamins. Their C-terminal CaaX motif undergoes farnesylation, aaX cleavage and carboxymethylation. Only lamin A is further cleaved 15 amino acids away from its farnesylated cysteine by the protease Zmpste24 [9]. Recent studies used fluorescence microscopy techniques in mammalian cells to show that A-type and B-t...
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