Molecular Biology of the Cell最新文献

The aggresome is a perinuclear structure that sequesters misfolded proteins. It is implicated in various neurodegenerative diseases. The perinuclear structure enriched with protein interacting with C kinase 1 (PICK1) was found to be inducible by cellular stressors, colocalizing with microtubule-organizing center markers and ubiquitin, hence classifying it as an aggresome. Sodium arsenite but not arsenate was found to potently induce aggresome formation through an integrated stress response-independent pathway. In HEK293T cells, under arsenite stress, PICK1 localization to the aggresome was prioritized, and formation of PICK1 homodimers was favored. Additionally, PICK1 could enhance protein entry into aggresomes. This study shows that arsenite can induce the formation of both RNA stress granules and aggresomes at the same time, and that PICK1 shows conditional localization to aggresomes, suggesting a possible involvement of PICK1 in neurodegenerative diseases.

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type versus functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both two-dimensional and three-dimensional cell migration, while the SAP-domain function is important selectively for three-dimensional cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction with MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF-SRF gene signature in pair-matched distant metastases versus primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human BC, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in BC.

Viruses use multiple strategies to successfully generate progeny and overcome host defenses. In recent years, it has become increasingly evident that epigenetic mechanisms of host gene regulation are vulnerable to viral manipulation. In the form of histone mimicry, viral invasion of host chromatin is a striking example of how viruses have evolved to invade every aspect of cellular function for viral benefit. In this perspective, we will review how three viruses-influenza A, SARS-CoV-2, and Cotesia plutellae bracovirus-use histone mimicry to promote viral success through immune evasion. These examples highlight the importance of this burgeoning field and point toward the wealth of knowledge we have yet to uncover.

Nde1 is a cytoplasmic dynein regulatory protein with important roles in vertebrate brain development. One noteworthy function is in the nuclear oscillatory behavior in neural progenitor cells, the control and mechanism of which remain poorly understood. Nde1 contains multiple phosphorylation sites for the cell cycle-dependent protein kinase CDK1, though the function of these sites is not well understood. To test their role in brain development, we expressed phosphorylation-state mutant forms of Nde1 in embryonic rat brains using in utero electroporation. We find that Nde1 T215 and T243 phosphomutants block apical interkinetic nuclear migration (INM) and, consequently, mitosis in radial glial progenitor cells. Another Nde1 phosphomutant at T246 also interfered with mitotic entry without affecting INM, suggesting a more direct role for Nde1 T246 in mitotic regulation. We also found that the Nde1 S214F mutation, which is associated with schizophrenia, inhibits Cdk5 phosphorylation at an adjacent residue which causes alterations in neuronal lamination. These results together identify important new roles for Nde1 phosphorylation in neocortical development and disease, and represent the first evidence for Nde1 phosphorylation roles in INM and neuronal lamination.