Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Tsukuba, Takayuki; Yamaguchi, Yu; Kadowaki, Tomoko

doi:10.3390/ijms22147691

Cited by 12 publications

(9 citation statements)

References 67 publications

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“…Rab44 is a member of the large Rab GTPase family that encodes an N-terminal EF-hand domain, a coiled-coil domain, and a C-terminal Rab-GTPase domain with a molecular mass of approximately 110 kDa [ 14 , 15 ]. Previously, our research group had initially identified an upregulated Rab44 protein during osteoclast differentiation [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

Noguromi

Yamaguchi²,

Satô³

et al. 2023

IJMS

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Rab44 was recently identified as an atypical Rab GTPase that possesses EF-hand and coiled-coil domains at the N-terminus, and a Rab-GTPase domain at the C-terminus. Rab44 is highly expressed in immune-related cells such as mast cells, macrophages, osteoclasts, and granulocyte-lineage cells in the bone marrow. Therefore, it is speculated that Rab44 is involved in the inflammation and differentiation of immune cells. However, little is known about the role of Rab44 in inflammation. In this study, we showed that Rab44 was upregulated during the early phase of differentiation of M1- and M2-type macrophages. Rab44-deficient mice exhibited impaired tumor necrosis factor alpha and interleukin-10 production after lipopolysaccharide (LPS) stimulation. The number of granulocytes in Rab44-deficient mice was lower, but the lymphocyte count in Rab44-deficient mice was significantly higher than that in wild-type mice after LPS stimulation. Moreover, Rab44-deficient macrophages showed impaired nickel-induced toxicity, and Rab44-deficient mice showed impaired nickel-induced hypersensitivity. Upon nickel hypersensitivity induction, Rab44-deficient mice showed different frequencies of immune cells in the blood and ears. Thus, it is likely that Rab44 is implicated in immune cell differentiation and inflammation, and Rab44 deficiency induces impaired immune responses to nickel allergies.

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Section: Introductionmentioning

confidence: 99%

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

Noguromi

Yamaguchi²,

Satô³

et al. 2023

IJMS

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“…When bound to its respective receptors on the surface of the endoplasmic reticulum (ER), IP 3 promotes a transient release of Ca 2+ from ER stores and a subsequent increase in cytosolic Ca 2+ concentrations 4 . This initial wave of Ca 2+ mobilization is essential for mast cell degranulation, a process reliant on SNARE fusion proteins which require Ca 2+ ‐sensitive accessory proteins such as Rab GTPases and synaptotagmins 5,6 . This sustained elevation in cytosolic Ca 2+ concentrations is also essential for the activation of critical proinflammatory transcription factors such as nuclear factor‐κB (NFκB) and nuclear factor of activated T cells (NFAT) and the subsequent secretion of various cytokines and chemokines, 7–9 augmenting the early phase allergic response.…”

Section: Introductionmentioning

confidence: 99%

Acute activation of SERCA with CDN1163 attenuates IgE‐mediated mast cell activation through selective impairment of ROS and p38 signaling

et al. 2023

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Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE‐mediated mast cell activation leads to a rapid mobilization of Ca2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca2+ concentrations. Among these is sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA), which functions to maintain low cytosolic Ca2+ concentrations by actively transporting cytosolic Ca2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen‐activated mast cells using IgE‐sensitized bone marrow‐derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL‐6, IL‐13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation.

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“…Rab proteins are classified into two groups: conventional “small” Rab proteins, including Rab1‐43, and atypical “large” Rab proteins, including Rab44, Rab45/RASEF, and Rab46 13–16 . The former members encode the Rab domain and exhibit molecular weights of approximately 20–30 kDa.…”

Section: Introductionmentioning

confidence: 99%

Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling

Tanimoto,

Yamaguchi,

Kadowaki

et al. 2023

J of Cellular Biochemistry

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Skeletal muscle is composed of multinucleated myotubes formed by the fusion of mononucleated myoblasts. Skeletal muscle differentiation, termed as myogenesis, have been investigated using the mouse skeletal myoblast cell line C2C12. It has been reported that several “small” Rab proteins, major membrane‐trafficking regulators, possibly regulate membrane protein transport in C2C12 cells; however, the role of Rab proteins in myogenesis remains unexplored. Rab44, a member of “large” Rab GTPases, has recently been identified as a negative regulator of osteoclast differentiation. In this study, using C2C12 cells, we found that Rab44 expression was upregulated during myoblast differentiation into myotubes. Knockdown of Rab44 enhanced myoblast differentiation and myotube formation. Consistent with these results, Rab44 knockdown in myoblasts increased expression levels of several myogenic marker genes. Rab44 knockdown increased the surface accumulation of myomaker and myomixer, two fusogenic proteins required for multinucleation, implying enhanced cell fusion. Conversely, Rab44 overexpression inhibited myoblast differentiation and tube formation, accompanied by decreased expression of some myogenic markers. Furthermore, Rab44 was found to be predominantly localized in lysosomes, and Rab44 overexpression altered the number and size of lysosomes. Considering the underlying molecular mechanism, Rab44 overexpression impaired the signaling pathway of the mechanistic target of rapamycin complex1 (mTORC1) in C2C12 cells. Namely, phosphorylation levels of mTORC1 and downstream mTORC1 substrates, such as S6 and P70‐S6K, were notably lower in Rab44 overexpressing cells than those in control cells. These results indicate that Rab44 negatively regulates myoblast differentiation into myotubes by controlling fusogenic protein transport and mTORC1 signaling.

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Large Rab GTPases: Novel Membrane Trafficking Regulators with a Calcium Sensor and Functional Domains

Cited by 12 publications

References 67 publications

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

Rab44 Deficiency Induces Impaired Immune Responses to Nickel Allergy

Acute activation of SERCA with CDN1163 attenuates IgE‐mediated mast cell activation through selective impairment of ROS and p38 signaling

Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling

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