Jin Ramon U, Mills Jason C
Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Cell Sci. 2014 Mar 1;127(Pt 5):1018-32. doi: 10.1242/jcs.138776. Epub 2014 Jan 10.
As they mature, professional secretory cells like pancreatic acinar and gastric chief cells induce the transcription factor MIST1 (also known as BHLHA15) to substantially scale up production of large secretory granules in a process that involves expansion of apical cytoplasm and redistribution of lysosomes and mitochondria. How a scaling factor like MIST1 rearranges cellular architecture simply by regulating expression levels of its transcriptional targets is unknown. RAB26 is a MIST1 target whose role in MIST1-mediated secretory cell maturation is also unknown. Here, we confirm that RAB26 expression, unlike most Rabs which are ubiquitously expressed, is tissue specific and largely confined to MIST1-expressing secretory tissues. Surprisingly, functional studies showed that RAB26 predominantly associated with LAMP1/cathepsin D lysosomes and not directly with secretory granules. Moreover, increasing RAB26 expression - by inducing differentiation of zymogen-secreting cells or by direct transfection - caused lysosomes to coalesce in a central, perinuclear region. Lysosome clustering in turn caused redistribution of mitochondria into distinct subcellular neighborhoods. The data elucidate a novel function for RAB26 and suggest a mechanism for how cells could increase transcription of key effectors to reorganize subcellular compartments during differentiation.
随着胰腺腺泡细胞和胃主细胞等成熟的专业分泌细胞的发育，它们会诱导转录因子MIST1（也称为BHLHA15）大量增加大型分泌颗粒的产生，这一过程涉及顶端细胞质的扩张以及溶酶体和线粒体的重新分布。像MIST1这样的缩放因子如何仅通过调节其转录靶标的表达水平来重新排列细胞结构尚不清楚。RAB26是MIST1的一个靶标，其在MIST1介导的分泌细胞成熟中的作用也不清楚。在这里，我们证实，与大多数普遍表达的Rabs不同，RAB26的表达具有组织特异性，并且主要局限于表达MIST1的分泌组织。令人惊讶的是，功能研究表明，RAB26主要与LAMP1/组织蛋白酶D溶酶体相关，而不直接与分泌颗粒相关。此外，通过诱导分泌酶原的细胞分化或直接转染来增加RAB26的表达，会导致溶酶体在核周中央区域聚集。溶酶体聚集进而导致线粒体重新分布到不同的亚细胞区域。这些数据阐明了RAB26的一种新功能，并提出了一种机制，即细胞如何在分化过程中增加关键效应因子的转录以重新组织亚细胞区室。
