LINCing Senescence and Nuclear Envelope Changes

Abstract

The nuclear envelope (NE) has emerged as a nexus for cellular organization, signaling, and survival. Beyond its role as a barrier to separate the nucleoplasm from the cytoplasm, the NE’s role in supporting and maintaining a myriad of other functions has made it a target of study in many cellular processes, including senescence. The nucleus undergoes dramatic changes in senescence, many of which are driven by changes in the NE. Indeed, Lamin B1, a key NE protein that is consistently downregulated in senescence, has become a marker for senescence. Other NE proteins have also been shown to play a role in senescence, including LINC (linker of nucleoskeleton and cytoskeleton) complex proteins. LINC complexes span the NE, forming physical connections between the cytoplasm to the nucleoplasm. In this way, they integrate nuclear and cytoplasmic mechanical signals and are essential not only for a variety of cellular functions but are needed for cell survival. However, LINC complex proteins have been shown to have a myriad of functions in addition to forming a LINC complex, often existing as nucleoplasmic or cytoplasmic soluble proteins in a variety of isoforms. Some of these proteins have now been shown to play important roles in DNA repair, cell signaling, and nuclear shape regulation, all of which are important in senescence. This review will focus on some of these roles and highlight the importance of LINC complex proteins in senescence.

Mechanotransduction and epigenetic modulations of chromatin: Role of mechanical signals in gene regulation

“…Nesprin-1 and -2 bind to the actin filaments by their N-terminal calponin homology domain and also associate with microtubules indirectly via kinesin and dynein. 177,178 Nesprin-3, much smaller than nesprin-1/-2, interacts indirectly with intermediate filaments via an adaptor protein, plectin. 175,177,178 Also, nesprin-4 associates with motor protein kinesin-1 and the microtubule network and has a role in nuclear positioning.…”

“…177,178 Nesprin-3, much smaller than nesprin-1/-2, interacts indirectly with intermediate filaments via an adaptor protein, plectin. 175,177,178 Also, nesprin-4 associates with motor protein kinesin-1 and the microtubule network and has a role in nuclear positioning. Another isoform of nesprin is LRMP (lymphoid-restricted membrane protein), whose cytoskeletal interaction is yet to be identified.…”

“…169,177,183 SUN 1/2 are expressed in various tissues, whereas SUN 3, 4, and 5 are expressed only in the testis. 183 SUN 1 is associated with telomere tethering and meiotic homologous recombination, 178 whereas SUN 2 interacts with Rab5 (a monomeric GTPase) and functions in endocytosis. 177 SUN 1 and 2 also play a vital role in nuclear anchorage, migration, and mechanotransduction.…”

“…177 SUN 1 and 2 also play a vital role in nuclear anchorage, migration, and mechanotransduction. 178 SUN proteins bind to the nuclear intermediate filament, lamins that are responsible for various nuclear functions, including stiffness, size, transcriptional regulation, and epigenetic status (Figure 3).…”

“…Six different isoforms of mammalian nesprins have been identified. Nesprin‐1 and ‐2 bind to the actin filaments by their N‐terminal calponin homology domain and also associate with microtubules indirectly via kinesin and dynein 177,178 . Nesprin‐3, much smaller than nesprin‐1/‐2, interacts indirectly with intermediate filaments via an adaptor protein, plectin 175,177,178 .…”