Jcb_201409047 1..12
نویسندگان
چکیده
Correspondence to Gregg G. Gundersen: [email protected] Abbreviations used in this paper: ABD, actin-binding domain; CH, calponin homology; KASH, Klarsicht, ANC-1, and Syne homology; LINC, linker of nucleoskeleton and cytoskeleton; SR, spectrin repeat; SUN, Sad1 and UNC-84; TAN, transmembrane actin–associated nuclear. Introduction The linker of nucleoskeleton and cytoskeleton (LINC) complex is widely recognized as the major means by which the nucleus is mechanically linked to the cytoskeleton in eukaryotic cells. It is composed of Klarsicht, ANC-1, and Syne homology (KASH) domain proteins in the outer nuclear membrane and Sad1 and UNC-84 (SUN) domain proteins in the inner nuclear membrane (Fig. 1). The KASH domain projects into the perinuclear space between the inner and outer nuclear membranes, where it interacts with the SUN domain of SUN proteins. This interaction prevents the KASH protein from diffusing out of the outer nuclear membrane into the contiguous ER. KASH proteins extend into the cytoplasm and allow the LINC complex to bind to different cytoskeletal elements and signaling molecules. SUN proteins in turn are localized in the inner nuclear membrane, anchoring the LINC complex in the nucleus by interactions with A-type lamins, chromatin-binding proteins, and other proteins. At its core, the LINC complex is a two-membrane adhesive assembly that is capable of transmitting mechanical force across the nuclear envelope. This capability is adapted for a diverse range of functions including moving the nucleus, maintaining the centrosome–nucleus connection, shaping the nucleus, signal transduction, DNA repair, and moving chromosomes within the nucleus (Burke and Roux, 2009; Starr and Fridolfsson, 2010). This functional diversity is achieved by assembling the LINC complex from distinct KASH proteins that interact with different cytoskeletal filaments and by associating with accessory factors. The LINC complex must be dynamic in order to switch between these functions, and to allow assembly of higher-ordered arrays that can transmit force to the nucleus as a whole or, alternatively, into the nucleus. We review the core LINC complex and interacting partners that alter cytoskeletal functionality and reinforce the core complex to permit force transduction. We consider how the LINC complex is differentially anchored for transmitting force to or into the nucleus. Furthermore, we examine data revealing that LINC complex components interact with signaling molecules, which suggests a role in signal transduction. Finally, we examine higher-ordered assemblies of LINC complexes and the role that accessory and anchoring proteins play in their formation and function. We do not address the function of short isoforms of KASH proteins that are generated by alternative transcriptional start sites or splicing, as these forms either do not localize to the nuclear membrane (KASH-less isoforms) or are unlikely to form LINC complexes, given their localization in the inner nuclear membrane (see Rajgor et al., 2012 for further discussion). Additionally, we refer the reader to reviews that cover other aspects of the LINC complex such as the discovery of its components and functions (Starr and Fridolfsson, 2010), threedimensional structure (Sosa et al., 2013), role in nuclear positioning (Gundersen and Worman, 2013) and meiosis (Hiraoka and Dernburg, 2009), and association with disease (Burke and Stewart, 2014). The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of outer and inner nuclear membrane Klarsicht, ANC-1, and Syne homology (KASH) and Sad1 and UNC-84 (SUN) proteins, respectively, connects the nucleus to cytoskeletal filaments and performs diverse functions including nuclear positioning, mechanotransduction, and meiotic chromosome movements. Recent studies have shed light on the source of this diversity by identifying factors associated with the complex that endow specific functions as well as those that differentially anchor the complex within the nucleus. Additional diversity may be provided by accessory factors that reorganize the complex into higher-ordered arrays. As core components of the LINC complex are associated with several diseases, understanding the role of accessory and anchoring proteins could provide insights into pathogenic mechanisms. Accessorizing and anchoring the LINC complex for multifunctionality
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تاریخ انتشار 2014