<b>M98K-OPTN induces transferrin receptor degradation and RAB12</b>-<b>mediated autophagic death in retinal ganglion cells</b>

Sirohi, Kapil; Chalasani, Madhavi Latha Somaraju; Sudhakar, Cherukuri; Kumari, Asha; Radha, Vegesna; Swarup, Ghanshyam

doi:10.4161/auto.23458

Cited by 73 publications

(120 citation statements)

References 57 publications

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“…We have recently shown that Rab12 enhances constitutive degradation of the Tfn receptor and the PAT4 amino acid transporter by controlling a unique pathway of cargo transport from the ERC to lysosomes (23,44,45). We and others also showed that Rab12 indirectly stimulates autophagy (45,46). Finally, in a recent work, Rab12 was shown to control retrograde transport of the Shiga toxin from the plasma membrane to the TGN (47).…”

Section: Discussionmentioning

confidence: 94%

Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP–Dynein Complex

Efergan

Azouz

Klein

et al. 2016

The Journal of Immunology

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Secretory granule (SG) transport is a critical step in regulated exocytosis including degranulation of activated mast cells. The latter process results in the release of multiple inflammatory mediators that play key roles in innate immunity, as well as in allergic responses. In this study, we identified the small GTPase Rab12 as a novel regulator of mast cell SG transport, and we provide mechanistic insights into its mode of action. We show that Rab12 is activated in a stimulus-dependent fashion and promotes microtubule-dependent retrograde transport of the SGs in the activated cells. We also show that this minus end transport of the SGs is mediated by the RILP–dynein complex and identify RILP as a novel effector of Rab12. Finally, we show that Rab12 negatively regulates mast cell degranulation. Taken together, our results identify Rab12 as a novel regulator of mast cell responses and disclose for the first time, to our knowledge, the mechanism of retrograde transport of the mast cell SGs.

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Section: Discussionmentioning

confidence: 94%

Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP–Dynein Complex

Efergan

Azouz

Klein

et al. 2016

The Journal of Immunology

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“…Alterations in autophagy activity have been proposed as an important mechanism for ALS [36][37][38] and glaucoma. 39,40 However, up to now, a unifying mechanism that can satisfactorily explain the pathogenesis of these mutations and diseases remains to be identified. We showed that 210 to 410D and E50K whose deletion and mutation were outside the UbBD functioned as the WT OPTN; however, the UbBD mutants such as 210 to 520D, 411 to 520D, UbBDD, E478G, and D474N interfered with the OPTN-mediated degradation of misfolded IBs.…”

Section: Discussionmentioning

confidence: 99%

“…Another second group mutant M98K was found to increase autophagy function and caused aberrant degradation of the transferrin receptor. 39 Taken together, it is tempting to hypothesize that mutations in OPTN may lead to diseases by tilting the balance of the autophagy activity. More studies are certainly required to further clarify this important issue.…”

Section: Discussionmentioning

confidence: 99%

Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism

et al. 2015

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OPTN (optineurin) is an autophagy receptor and mutations in the OPTN gene result in familial glaucoma (E50K) and amyotrophic lateral sclerosis (ALS) (E478G). However, the mechanisms through which mutant OPTN leads to human diseases remain to be characterized. Here, we demonstrated that OPTN colocalized with inclusion bodies (IBs) formed by mutant HTT/huntingtin protein (mHTT) in R6/2 transgenic mice and IBs formed by 81QNmHTT (nuclear form), 109QmHTT (cytoplasmic form) or the truncated form of TARDBP/TDP-43 (TARDBP(ND251)) in Neuro2A cells. This colocalization required the ubiquitin (Ub)-binding domain (UbBD, amino acids 424 to 511) of OPTN. Overexpression of wild-type (WT) OPTN decreased IBs through K63-linked polyubiquitin-mediated autophagy. E50K or 210 to 410Δ (with amino acids 210 to 410 deleted) whose mutation or deletion was outside the UbBD decreased the IBs formed by 109QmHTT or TARDBP(ND251), as was the case with WT OPTN. In contrast, UbBD mutants, including E478G, D474N, UbBDΔ, 411 to 520Δ and 210 to 520Δ, increased accumulation of IBs. UbBD mutants (E478G, UbBDΔ) retained a substantial ability to interact with WT OPTN, and were found to colocalize with polyubiquitinated IBs, which might occur indirectly through their WT partner in a WT-mutant complex. They decreased autophagic flux evidenced by alteration in LC3 level and turnover and in the number of LC3-positive puncta under stresses like starvation or formation of IBs. UbBD mutants exhibited a weakened interaction with MYO6 (myosin VI) and TOM1 (target of myb1 homolog [chicken]), important for autophagosome maturation, in cells or sorted 109QmHtt IBs. Taken together, our data indicated that UbBD mutants acted as dominant-negative traps through the formation of WT-mutant hybrid complexes to compromise the maturation of autophagosomes, which in turn interfered with OPTN-mediated autophagy and clearance of IBs.

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“…In particular, Rab12 has been identified recently as a key player in autophagy, and its depletion severely impairs the autophagic process (2,3). To function in autophagy, Rab12 needs to become GTP-loaded and activated, and the DENN (differentially expressed in normal and neoplastic cells) protein DENND3 was identified as its guanine nucleotide exchange factor (GEF) 2 (4).…”

mentioning

confidence: 99%

“…E-mail: scaplan@ unmc.edu. 2 The abbreviations used are: GEF, guanine nucleotide exchange factor; ULK, Unc-51-like kinase.…”

mentioning

confidence: 99%

Into the linker's DENN: A tyrosine's control of autophagy

Caplan

2017

Journal of Biological Chemistry

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Edited by Thomas Sö llnerThe small GTP-binding protein Rab12 plays an important role in the initiation of starvation-induced macroautophagy (autophagy) and is activated by the guanine-nucleotide exchange factor DENND3. However, the molecular mechanism by which DENND3 becomes activated has remained elusive. Xu and McPherson now identify a novel mechanism of DENND3 intramolecular binding that is regulated by the phosphorylation of a single tyrosine residue.Autophagy is a means of selectively marking cellular organelles for lysosomal degradation and plays a vital role in the recycling of proteins during stress caused by nutrient deprivation (1). During this process, various protein complexes (known as initiation and nucleation complexes) first localize to a membrane-phagophore assembly site and then recruit additional autophagy-related proteins to elongate the phagophore membrane. Eventually, the phagophore closes into an autophagosome, which ultimately fuses with the lysosome. Despite the considerable advances that have been made in understanding the molecular processes of autophagosome formation and its fusion with lysosomes, the mechanisms by which nutrient deprivation induces the initiation of this process remains poorly understood.The Rab family of small GTP-binding proteins plays an essential role in membrane-trafficking pathways, including the control of various steps of autophagy. In particular, Rab12 has been identified recently as a key player in autophagy, and its depletion severely impairs the autophagic process (2, 3). To function in autophagy, Rab12 needs to become GTP-loaded and activated, and the DENN (differentially expressed in normal and neoplastic cells) protein DENND3 was identified as its guanine nucleotide exchange factor (GEF) 2 (4). As the DENN domain-containing proteins comprise the largest family of Rab-GTP exchange factors, understanding their mechanisms of action has ramifications beyond DENND3 and Rab12. To date, the molecular mechanisms of DENND3 activation and its induction by nutrient deprivation are not well understood. It is known that serum starvation leads to the activation of a kinase known as Unc-51-like kinase (ULK), which subsequently phosphorylates serines 554 and 572 on DENND3 (5). This, in turn, allows recruitment of the adapter protein, 14-3-3, to DENND3, which somehow leads to up-regulation of DENND3 GEF activity toward Rab12. However, whether there is a separate mechanism to more precisely regulate DENND3 in response to serum starvation remains a central and unanswered question.In this exciting paper by Xu and McPherson (6), the authors shed new light on the mechanism by which the Rab12 GEF, DENND3, becomes activated upon serum starvation. Because the "linker" region of DENND3 (which extends from amino acids 520 -973) contains both serines 554 and 572 that are phosphorylated by ULK, the authors initially hypothesized that the linker region might interact with the DENN domain and inhibit GEF activity and that ULK phosphorylation might release this auto-inhibition. Using...

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M98K-OPTN induces transferrin receptor degradation and RAB12-mediated autophagic death in retinal ganglion cells

Cited by 73 publications

References 57 publications

Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP–Dynein Complex

Rab12 Regulates Retrograde Transport of Mast Cell Secretory Granules by Interacting with the RILP–Dynein Complex

Mutations in the ubiquitin-binding domain of OPTN/optineurin interfere with autophagy-mediated degradation of misfolded proteins by a dominant-negative mechanism

Into the linker's DENN: A tyrosine's control of autophagy

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