While continuous with the remaining Endoplasmic Reticulum (ER) membrane, the INM has a distinct set of proteins ( Pawar and Kutay, 2021). Chromosome interactions involve primarily proteins at the inner nuclear membrane (INM), which together with the outer nuclear membrane (ONM), forms the NE. These interactions influence a myriad of cellular processes, from gene regulation and repair to cell motility and fate ( Mekhail and Moazed, 2010). The organization of eukaryotic chromosomes within the cell nucleus depends on regulated and dynamic interactions with the nuclear envelope (NE). These findings uncover a central role of proteolysis in INM protein homeostasis. Importantly, accumulation of non-degradable SUN2 results in aberrant nuclear architecture, vulnerability to DNA damage and increased lagging chromosomes in mitosis. Ubiquitinated SUN2 is membrane extracted by the AAA ATPase p97 and delivered to the proteasome for degradation. Upon binding to phosphorylated SUN2, SCF βTrCP promotes its ubiquitination. We show that Casein Kinase 2 and the C-terminal domain Nuclear Envelope Phosphatase 1 (CTDNEP1) have opposing effects on SUN2 levels by regulating SUN2 binding to the ubiquitin ligase Skp/Cullin1/F-Box βTrCP (SCF βTrCP). Here, we describe a mechanism of regulated degradation of the INM SUN domain-containing protein 2 (SUN2). However, mechanisms controlling the levels and turnover of INM proteins remain unknown. Mutations in INM proteins interfering with these interactions result in disease. Nuclear architecture and functions depend on dynamic interactions between nuclear components (such as chromatin) and inner nuclear membrane (INM) proteins.
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