RESUMEN
Cellular disturbances that cause accumulation of misfolded proteins in the endoplasmic reticulum (ER) lead to a condition referred to as "ER stress" and trigger the unfolded protein response (UPR), a signaling pathway that attempts to restore ER homeostasis. The complexity of UPR signaling can generate adaptive and apoptotic outputs, depending on the nature and duration of the ER stress. MicroRNAs (miRNAs), small non-coding RNAs that typically repress gene expression, have recently emerged as key gene regulators of the proadaptive/proapoptotic molecular switch emanating from the ER. Importantly, select miRNAs have been shown to directly regulate key UPR components.
Asunto(s)
Retículo Endoplásmico/fisiología , MicroARNs/metabolismo , Estrés Fisiológico , Animales , Apoptosis/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Humanos , Factores de Transcripción/genéticaRESUMEN
Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a multifaceted signaling system coordinating translational control and gene transcription to promote cellular adaptation and survival. Microribonucleic acids (RNAs; miRNAs), single-stranded RNAs that typically function as posttranscriptional modulators of gene activity, have been shown to inhibit translation of certain secretory pathway proteins during the UPR. However, it remains unclear whether miRNAs regulate UPR signaling effectors directly. In this paper, we report that a star strand miRNA, miR-30c-2* (recently designated miR-30c-2-3p), is induced by the protein kinase RNA activated-like ER kinase (PERK) pathway of the UPR and governs expression of XBP1 (X-box binding protein 1), a key transcription factor that augments secretory capacity and promotes cell survival in the adaptive UPR. These data provide the first link between an miRNA and direct regulation of the ER stress response and reveal a novel molecular mechanism by which the PERK pathway, via miR-30c-2*, influences the scale of XBP1-mediated gene expression and cell fate in the UPR.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , MicroARNs/metabolismo , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada/genética , Animales , Secuencia de Bases , Proteínas de Unión al ADN/genética , Células HeLa , Humanos , Ratones , MicroARNs/genética , Datos de Secuencia Molecular , Células 3T3 NIH , Factores de Transcripción del Factor Regulador X , Transducción de Señal , Factores de Transcripción/genética , Proteína 1 de Unión a la X-Box , eIF-2 Quinasa/genética , eIF-2 Quinasa/metabolismoRESUMEN
Stress in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), a signaling mechanism that allows cellular adaptation to ER stress by engaging pro-adaptive transcription factors and alleviating protein folding demand. One such transcription factor, X-box binding protein (XBP1), originates from the inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1) UPR stress sensor. XBP1 up-regulates a pool of genes involved in ER protein translocation, protein folding, vesicular trafficking and ER- associated protein degradation. Recent data suggest that the regulation of XBP1 expression and transcriptional activity may be a tissue- and stress-dependent phenomenon. Moreover, the intricacies involved in “fine-tuning” XBP1 activity in various settings are now coming to light. Here, we provide an overview of recent developments in understanding the regulatory mechanisms underlying XBP1 expression and activity and discuss the significance of these new insights.
