scholarly journals Lamin A buffers CK2 kinase activity to modulate aging in a progeria mouse model.

2019 ◽  
Vol 5 (3) ◽  
pp. eaav5078 ◽  
Author(s):  
Ying Ao ◽  
Jie Zhang ◽  
Zuojun Liu ◽  
Minxian Qian ◽  
Yao Li ◽  
...  
Keyword(s):  
Kinase Activity ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Lamin A ◽  
Catalytic Core ◽  
Prelamin A ◽  
Damage Repair ◽  
Nuclear Lamin ◽  
Activity Loss ◽  
Ck2 Kinase

Defective nuclear lamina protein lamin A is associated with premature aging. Casein kinase 2 (CK2) binds the nuclear lamina, and inhibiting CK2 activity induces cellular senescence in cancer cells. Thus, it is feasible that lamin A and CK2 may cooperate in the aging process. Nuclear CK2 localization relies on lamin A and the lamin A carboxyl terminus physically interacts with the CK2α catalytic core and inhibits its kinase activity. Loss of lamin A inLmna-knockout mouse embryonic fibroblasts (MEFs) confers increased CK2 activity. Conversely, prelamin A that accumulates inZmpste24-deficent MEFs exhibits a high CK2α binding affinity and concomitantly reduces CK2 kinase activity. Permidine treatment activates CK2 by releasing the interaction between lamin A and CK2, promoting DNA damage repair and ameliorating progeroid features. These data reveal a previously unidentified function for nuclear lamin A and highlight an essential role for CK2 in regulating senescence and aging.

scholarly journals Analysis of Prelamin A Biogenesis Reveals the Nucleus to be a CaaX Processing Compartment

2008 ◽  
Vol 19 (12) ◽  
pp. 5398-5408 ◽  
Author(s):  
Jemima Barrowman ◽  
Corinne Hamblet ◽  
Carolyn M. George ◽  
Susan Michaelis
Keyword(s):  
Posttranslational Modifications ◽  
Active Sites ◽  
Intracellular Localization ◽  
Premature Aging ◽  
Lamin A ◽  
Prelamin A ◽  
Processing Enzymes ◽  
Dual Localization ◽  
Endoproteolytic Cleavage ◽  
Er Membrane

Proteins establish and maintain a distinct intracellular localization by means of targeting, retention, and retrieval signals, ensuring most proteins reside predominantly in one cellular location. The enzymes involved in the maturation of lamin A present a challenge to this paradigm. Lamin A is first synthesized as a 74-kDa precursor, prelamin A, with a C-terminal CaaX motif and undergoes a series of posttranslational modifications including CaaX processing (farnesylation, aaX cleavage and carboxylmethylation), followed by endoproteolytic cleavage by Zmpste24. Failure to cleave prelamin A results in progeria and related premature aging disorders. Evidence suggests prelamin A is imported directly into the nucleus where it is processed. Paradoxically, the processing enzymes have been shown to reside in the cytosol (farnesyltransferase), or are ER membrane proteins (Zmpste24, Rce1, and Icmt) with their active sites facing the cytosol. Here we have reexamined the cellular site of prelamin A processing, and show that the mammalian and yeast processing enzymes Zmpste24 and Icmt exhibit a dual localization to the inner nuclear membrane, as well as the ER membrane. Our findings reveal the nucleus to be a physiologically relevant location for CaaX processing, and provide insight into the biology of a protein at the center of devastating progeroid diseases.

scholarly journals A complex containing p34cdc2 and cyclin B phosphorylates the nuclear lamin and disassembles nuclei of clam oocytes in vitro.

1991 ◽  
Vol 112 (4) ◽  
pp. 523-533 ◽  
Author(s):  
G Dessev ◽  
C Iovcheva-Dessev ◽  
J R Bischoff ◽  
D Beach ◽  
R Goldman
Keyword(s):  
Protein Kinase ◽  
Hela Cells ◽  
Kinase Activity ◽  
Nuclear Lamina ◽  
Cyclin B ◽  
Protein Kinase Activity ◽  
Nuclear Lamin ◽  
Single Protein ◽  
M Phase

Cell-free extracts prepared from activated clam oocytes contain factors which induce phosphorylation of the single 67-kD lamin (L67), disassemble clam oocyte nuclei, and cause chromosome condensation in vitro (Dessev, G., R. Palazzo, L. Rebhun, and R. Goldman. 1989. Dev. Biol. 131:469-504). To identify these factors, we have fractionated the oocyte extracts. The nuclear lamina disassembly (NLD) activity, together with a protein kinase activity specific for L67, appear as a single peak throughout a number of purification steps. This peak also contains p34cdc2, cyclin B, and histone H1-kinase activity, which are components of the M-phase promoting factor (MPF). The NLD/L67-kinase activity is depleted by exposure of this purified material to Sepharose conjugated to p13suc1, and is restored upon addition of a p34cdc2/p62 complex from HeLa cells. The latter complex phosphorylates L67 and induces NLD in the absence of other clam oocyte proteins. Our results suggest that a single protein kinase activity (p34cdc2-H1 kinase, identical with MPF) phosphorylates the lamin and is involved in the meiotic breakdown of the nuclear envelope in clam oocytes.

Prelamin A-mediated nuclear envelope dynamics in normal and laminopathic cells

2011 ◽  
Vol 39 (6) ◽  
pp. 1698-1704 ◽  
Author(s):  
Giovanna Lattanzi
Keyword(s):  
Nuclear Envelope ◽  
Accelerated Aging ◽  
Nuclear Lamina ◽  
Major Constituent ◽  
Lamin A ◽  
Post Translational Modifications ◽  
Prelamin A ◽  
Chromatin Dynamics ◽  
Chromatin Arrangement ◽  
And Function

Prelamin A is the precursor protein of lamin A, a major constituent of the nuclear lamina in higher eukaryotes. Increasing attention to prelamin A processing and function has been given after the discovery, from 2002 to 2004, of diseases caused by prelamin A accumulation. These diseases, belonging to the group of laminopathies and mostly featuring LMNA mutations, are characterized, at the clinical level, by different degrees of accelerated aging, and adipose tissue, skin and bone abnormalities. The outcome of studies conducted in the last few years consists of three major findings. First, prelamin A is processed at different rates under physiological conditions depending on the differentiation state of the cell. This means that, for instance, in muscle cells, prelamin A itself plays a biological role, besides production of mature lamin A. Secondly, prelamin A post-translational modifications give rise to different processing intermediates, which elicit different effects in the nucleus, mostly by modification of the chromatin arrangement. Thirdly, there is a threshold of toxicity, especially of the farnesylated form of prelamin A, whose accumulation is obviously linked to cell and organism senescence. The present review is focused on prelamin A-mediated nuclear envelope modifications that are upstream of chromatin dynamics and gene expression mechanisms regulated by the lamin A precursor.

scholarly journals SUN1 Interacts with Nuclear Lamin A and Cytoplasmic Nesprins To Provide a Physical Connection between the Nuclear Lamina and the Cytoskeleton

2006 ◽  
Vol 26 (10) ◽  
pp. 3738-3751 ◽  
Author(s):  
Farhana Haque ◽  
David J. Lloyd ◽  
Dawn T. Smallwood ◽  
Carolyn L. Dent ◽  
Catherine M. Shanahan ◽  
...  
Keyword(s):  
Binding Protein ◽  
Nuclear Lamina ◽  
Integral Membrane Protein ◽  
Actin Binding ◽  
Lamin A ◽  
Terminal Domain ◽  
Cytoskeletal Network ◽  
Nuclear Lamin ◽  
Nuclear Component ◽  
Two Hybrid

ABSTRACT Nuclear migration and positioning within cells are critical for many developmental processes and are governed by the cytoskeletal network. Although mechanisms of nuclear-cytoskeletal attachment are unclear, growing evidence links a novel family of nuclear envelope (NE) proteins that share a conserved C-terminal SUN (Sad1/UNC-84 homology) domain. Analysis of Caenorhabditis elegans mutants has implicated UNC-84 in actin-mediated nuclear positioning by regulating NE anchoring of a giant actin-binding protein, ANC-1. Here, we report the identification of SUN1 as a lamin A-binding protein in a yeast two-hybrid screen. We demonstrate that SUN1 is an integral membrane protein located at the inner nuclear membrane. While the N-terminal domain of SUN1 is responsible for detergent-resistant association with the nuclear lamina and lamin A binding, lamin A/C expression is not required for SUN1 NE localization. Furthermore, SUN1 does not interact with type B lamins, suggesting that NE localization is ensured by binding to an additional nuclear component(s), most likely chromatin. Importantly, we find that the luminal C-terminal domain of SUN1 interacts with the mammalian ANC-1 homologs nesprins 1 and 2 via their conserved KASH domain. Our data provide evidence of a physical nuclear-cytoskeletal connection that is likely to be a key mechanism in nuclear-cytoplasmic communication and regulation of nuclear position.

scholarly journals Nucleoplasmic localization of prelamin A: implications for prenylation-dependent lamin A assembly into the nuclear lamina.

1992 ◽  
Vol 89 (7) ◽  
pp. 3000-3004 ◽  
Author(s):  
R. J. Lutz ◽  
M. A. Trujillo ◽  
K. S. Denham ◽  
L. Wenger ◽  
M. Sinensky
Keyword(s):  
Nuclear Lamina ◽  
Lamin A ◽  
Prelamin A

scholarly journals A new paradigm for Prelamin A proteolytic processing by ZMPSTE24: the upstream SY^LL cleavage occurs first and there is no CaaX processing by ZMPSTE24

2020 ◽  
Author(s):  
Laiyin Nie ◽  
Eric Spear ◽  
Timothy D. Babatz ◽  
Andrew Quigley ◽  
Yin Yao Dong ◽  
...  
Keyword(s):  
Nuclear Lamina ◽  
Proteolytic Processing ◽  
Lamin A ◽  
New Paradigm ◽  
Post Translational Modifications ◽  
Prelamin A ◽  
Zinc Metalloprotease ◽  
Sequence Of Events ◽  
C Terminus

AbstractHuman ZMPSTE24, an integral membrane zinc metalloprotease, is required for conversion of prelamin A to mature lamin A, a component of the nuclear lamina and failure of this processing causes premature ageing disorders. ZMPSTE24 has also been implicated in both type 2 diabetes mellitus and in viral-host response mechanisms, but to date its only confirmed substrate is the precursor for lamin A. Prelamin A is thought to undergo four C-terminal post-translational modifications in the following order: farnesylation, SIM tripeptide cleavage, carboxymethylation and upstream “SY^LL” cleavage. Here we present evidence that the sequence of events does not follow the accepted dogma. We assessed cleavage of long human prelamin A sequence peptides by purified human ZMPSTE24 combined with FRET and mass spectrometry to detect products. Surprisingly, we found that the “SY^LL” cleavage occurs before and independent of the C-terminal CSIM modifications. We also found that ZMPSTE24 does not perform the predicted C^SIM tripeptide cleavage, but rather it removes an IM dipeptide. ZMPSTE24 can perform a tripeptide cleavage with a canonical CaaX box (C: cysteine; a: aliphatic; X: any residue), but the C-terminus of prelamin A is not a true CaaX sequence. Regardless of the C-terminal modifications of prelamin A, ZMPSTE24 can perform upstream SY^LL cleavage, thus removing the unwanted farnesylated C-terminus. Therefore, it is failure of SY^LL cleavage, not the C-terminal processing that is the likely cause of progeroid disorders.

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