RAB26 coordinates lysosome traffic and mitochondrial localization

Abstract

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 zymogensecreting 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.

A single transcription factor is sufficient to induce and maintain secretory cell architecture

“…We show here, and we and others have shown previously, that trafficking of lysosomes and mitochondria is regulated by MIST1 (Luo et al 2005;Jin and Mills 2014). Autophagy control is likely critical in longlived secretory cells with high anabolic demands for producing protein; old organelles must be recycled efficiently, but there may be specific mechanisms also to preserve secretory granules from degradation until a signal to secrete is received.…”

“…Manual annotation (Supplemental Table S2) indicates that a large cohort of MIST1 targets regulates lysosomal trafficking and/or autophagic function: 5330417C22Rik, Copz2, Rab26, Wdyhv1, Ostm1, and Trabd (Lange et al 2006;Wang et al 2009;Behrends et al 2010;Deng et al 2010;Shtutman et al 2011;Jin and Mills 2014;Pandruvada et al 2015). We show here, and we and others have shown previously, that trafficking of lysosomes and mitochondria is regulated by MIST1 (Luo et al 2005;Jin and Mills 2014).…”

“…Autophagy control is likely critical in longlived secretory cells with high anabolic demands for producing protein; old organelles must be recycled efficiently, but there may be specific mechanisms also to preserve secretory granules from degradation until a signal to secrete is received. We characterized the lysosome and mitochondrial trafficking properties of RAB26 (Jin and Mills 2014) previously, and others recently have shown it to help regulate trafficking to autophagy (Binotti et al 2015).…”

“…Figure 6A ranks the putative MIST1 targets in decreasing order of fulfilling the filtering criteria. Two genes in the list, Rab26 and Copz2, have been shown previously to be direct targets of Mist1 Direnzo et al 2012;Jin and Mills 2014). Thus, we identified multiple core transcriptional targets of MIST1 that meet the following criteria: (1) Their expression is regulated by MIST1 in multiple organs, (2) their genes' regulatory elements are occupied by MIST1, (3) their expression is increased in in vivo gain-of-MIST1-function experiments, (4) their expression is decreased in in vivo loss-of-MIST1 experiments, (5) they are coexpressed in tissues where MIST1 is highly expressed, and (6) they are known to have function and localization consistent with roles as cellular effectors to induce and maintain cellular secretory architecture.…”

Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A

“…The early effects include reduced expression of several genes notable for high mRNA levels and highly restricted expression that boost the capacity of protein folding in the ER (Erp27 and Cabp2), direct transport to the Golgi complex (Tmed11), concentrate secretory proteins in the Golgi complex and condensing zymogen granules (Aqp12), organize the packaging of the secretory proteins (Gp2, Sycn, Cuzd1, and Zg16), and promote the proper organization of the apical cytoplasm (Rab26) (61). These gene expression defects establish the conditions for the subsequent disruption of cellular homeostasis.…”