RAB2 regulates the formation of autophagosome and autolysosome in mammalian cells

Abstract

Multiple sources contribute membrane and protein machineries to construct functional macroautophagic/autophagic structures. However, the underlying molecular mechanisms remain elusive. Here, we show that RAB2 connects the Golgi network to autophagy pathway by delivering membrane and by sequentially engaging distinct autophagy machineries. In unstressed cells, RAB2 resides primarily in the Golgi apparatus, as evidenced by its interaction and colocalization with GOLGA2/GM130. Importantly, autophagy stimuli dissociate RAB2 from GOLGA2 to interact with ULK1 complex, which facilitates the recruitment of ULK1 complex to form phagophores. Intriguingly, RAB2 appears to modulate ULK1 kinase activity to propagate signals for autophagosome formation. Subsequently, RAB2 switches to interact with autophagosomal RUBCNL/PACER and STX17 to further specify the recruitment of HOPS complex for autolysosome formation. Together, our study reveals a multivalent pathway in bulk autophagy regulation, and provides mechanistic insights into how the Golgi apparatus contributes to the formation of different autophagic structures.

Presynaptic precursor vesicles originate from thetrans-Golgi network, promoted by the small GTPase RAB2

“…However, we detected a 3fold increase in the incidence of somatic structures resembling autophagocytic organelles in rab2 mutants ( Fig. S5D), potentially interesting in connection with the previously reported function of RAB2 in autophagic degradative pathways (Ding et al, 2019;Fujita et al, 2017;Lorincz et al, 2017;Lund et al, 2018).…”

“…Of note, a subfraction of the ectopic LAMP1 accumulations in rab2 mutant were devoid of BRP signal and thus apparently not associated with early presynaptic precursor fields (Fig. S6C,D), potentially related to the previously described function of RAB2 in autophagic and lysosomal degradation (Ding et al, 2019;Fujita et al, 2017;Lorincz et al, 2017;Lund et al, 2018). In summary, these data suggest that at an early RAB2 dependent step of precursor biogenesis presynaptic proteins sort out of the Golgi on independent routes, separating active zone scaffold from SV/LAMP1 proteins.…”

“…Of note, this does not, however, imply that smaller RAB2 positive signals or low abundance RAB2 protein might not localize to other cellular compartments as previously reported for other cell types, e.g. fat cells, nephrocytes, salivary glands or muscles (Ding et al, 2019;Fujita et al, 2017;Lorincz et al, 2017;Lund et al, 2018).…”

Dexmedetomidine Alleviated Endoplasmic Reticulum Stress via Inducing ER-phagy in the Spinal Cord of Neuropathic Pain Model

“…In this study, we examined the expression level of FAM134B to evaluate the ER-phagy. FAM134B is an ER-resident receptor that facilitates ER degradation by autophagy via binding to autophagosomes (Murrow and Debnath, 2013;Khaminets et al, 2015;Grumati et al, 2018;Liang et al, 2018;Ding et al, 2019;Forrester et al, 2019;Wilkinson, 2019a,b). Our data showed that Grp78, FAM134B, p62, and cleaved caspase-3 were increased in the spinal cord of the SNL group compared with the sham group at postoperative days 7 and 14.…”

Rab2 drives axonal transport of dense core vesicles and lysosomal organelles

“…Recently, we and others reported that Rab2 is critical for biogenesis of mature degradative endoand autolysosomal compartments by controlling the fusion of late endosomes (LEs) with lysosomes and transport vesicles carrying lysosomal membrane proteins, and fusion of autophagosomes with endolysosomal organelles (Lorincz et al, 2017;Lund et al, 2018) (Ding et al, 2019).…”