Rheb localized on the Golgi membrane activates lysosome-localized mTORC1 at the Golgi–lysosome contact site

Hao, Feike; Kondo, Kazuhiko; Itoh, Takashi; Ikari, Sumiko; Nada, Shigeyuki; Okada, Masato; Noda, Tetsuji

doi:10.1242/jcs.208017

Cited by 67 publications

(75 citation statements)

References 64 publications

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“…Together with amino acid sensing signals from the cytosol, these cues converge on GATOR1/2 and lead to the recruitment of mTORC1 to the lysosome through interactions with a complex comprised of Ragulator and Rag GTPases . In addition, mitogenic signaling by phosphatidylinositol‐3‐kinase (PI3K) and Akt activate Rheb, which is required for activation of mTORC1 . As both mitogenic and metabolic arms are required for its activation, mTORC1 is selectively activated under conditions of nutrient sufficiency.…”

Section: Mtorc1 Coordinates Endocytic Membrane Traffic With Nutrient mentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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Section: Mtorc1 Coordinates Endocytic Membrane Traffic With Nutrient mentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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“…As an alternative to the possibility that Rheb dynamically visits the surface of lysosomes in order to activate mTORC1, it was recently reported that Rheb instead resides on the Golgi and activates mTORC1 via contact sites between the Golgi and lysosomes (Hao et al, 2018). However, this study relied on assessing the ability of heavily over-expressed, Golgi-targeted Rheb, to hyper-activate mTORC1 signaling.…”

Section: Evidence In Favor Of Dynamic Interactions Between Rheb and Ementioning

confidence: 99%

“…Adding to the confusion concerning the relationship between Rheb localization and function, it has also recently been proposed that Rheb instead resides on either the ER or Golgi and activates mTORC1 via contact sites between these organelles and lysosomes (Hao et al, 2018;Walton et al, 2018). These recent observations are paralleled by some older studies that also reported enrichment of over-expressed Rheb at the endoplasmic reticulum (Buerger et al, 2006;Hanker et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Weak Membrane Interactions Allow Rheb to Activate mTORC1 Signaling Without Major Lysosome Enrichment

Angarola

Ferguson

2019

Preprint

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Stable localization of the Rheb GTPase to lysosomes is thought to be required for activation of mTORC1 signaling. However, the lysosome targeting mechanisms for Rheb remain unclear. We therefore investigated the relationship between Rheb subcellular localization and mTORC1 activation. Surprisingly, we found that Rheb was undetectable at lysosomes. Nonetheless, functional assays in knockout human cells revealed that farnesylation of the C-terminal CaaX motif on Rheb was essential for Rheb-dependent mTORC1 activation. Although farnesylated Rheb exhibits partial endoplasmic reticulum localization, constitutively targeting Rheb to ER membranes did not support mTORC1 activation. Further systematic analysis of Rheb lipidation revealed that weak, nonselective, membrane interactions support Rheb-dependent mTORC1 activation without the need for a specific lysosome targeting motif. Collectively, these results argue against stable interactions of Rheb with lysosomes and instead that transient membrane interactions optimally allow Rheb to activate mTORC1 signaling.

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“…One of them is aligned with the recent realization and general trend in cell biology that material exchange and organelle biogenesis/remodeling occur at membrane contact sites involving different organelles [4]. Indeed, contact sites between the ER and mitochondria or the ER and the plasma membrane [5,6] have been reported as contributing to autophagosome biogenesis, whereas Golgi-lysosome contact sites may control signaling by mTOR, an upstream regulator of autophagy [7].…”

mentioning

confidence: 84%