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The Nuclear Transportation Routes of Membrane-Bound Transcription Factors


The Nuclear Transportation Routes of Membrane-Bound Transcription Factors

Yang Liu et al. Cell Commun Signal.


Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state. Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus. Upon specific signal recognition cues, some PM-bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. However, lipid-anchored PM-bound proteins enter the nucleus in their full length for depalmitoylation. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. Moreover, targeting intracellular movement pathways of disease-associated MTFs may significantly improve the survival of patients.

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Fig. 1
Fig. 1
The nuclear transportation routes of plasma membrane-bound proteins. (a1-a2) Some PM proteins are cleaved by regulated intramembrane proteolysis. The fragments facing to cytosol are released and relocated to the nucleus. (b1-b2) Some of them attach to the plasma membrane by palmitoylation. They release from the plasma membrane by depalmitoylation and then enter the nucleus upon signal induction. (c1-c5) Some proteins release from the membrane by endocytosis and then go to the Golgi. Through Golgi to ER retrograde trafficking, they are finally translocated into the nucleus
Fig. 2
Fig. 2
ER membrane-bound proteins are translocated into the nucleus directly. (a) Nuclear translocation by RUP. (a1) Proteins get ubiquitinated by ubiquitin ligase. (a2) The ubiquitinated precursor is then processed by a proteasome. The portion within the ER lumen and transmembrane span are degraded by proteasomes. (a3) The active segments enter the nucleus to regulate gene expression. (b) Nuclear translocation by auto-proteolysis. (b1-b2) ER membrane proteins undergo autocatalytic proteolysis, and then the liberated cytosolic fragments are translocated into the nucleus. (c) Nuclear translocation by alternative splicing. (c1) Unspliced mRNA transfers to the ER and is spliced by ER enzymes. (c2-c3) Protein fragments translated by spliced mRNA are transported to the nucleus to regulate gene expression
Fig. 3
Fig. 3
ER membrane-bound proteins relocate in the nucleus by trafficking to the Golgi. (a1-a2) ER membrane-located proteins are transported to the Golgi by COPII vesicles. (a3) Within the Golgi apparatus they are cleaved by Golgi-resident proteases. (a4) Finally, soluble cytosolic segments enter the nucleus to play a transcription regulation role

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