Structural basis for the activation of acid ceramidase

Gebai, A.; Gorelik, A.; Li, Zixian; Illés, K.; Nagar, Bhushan

doi:10.1038/s41467-018-03844-2

Cited by 76 publications

(80 citation statements)

References 74 publications

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“…The fact that the C24:1 acyl chain of nervonic acid increases the selectivity of RBM14 probes towards NC is in full agreement with the reported structural data for this enzyme, in which a 20Å deep, hydrophobic active site pocket determines the higher selectivity of NC towards long chain acyl ceramide substrates (23). Based on these considerations, the C24:1 acyl chain would be too long to fit into the 13Å cavity found in AC active site (24).…”

Section: Discussionsupporting

confidence: 88%

New fluorogenic probes for neutral and alkaline ceramidases

Casasampere

Bielsa

Riba

et al. 2019

Journal of Lipid Research

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New fluorogenic ceramidase substrates derived from the N-acyl modification of our previously reported probes (RBM14) are reported. While none of the new probes were superior to the known RBM14C12 as acid ceramidase substrates, the corresponding nervonic acid amide (RBM14C24:1) is an efficient and selective substrate for the recombinant human neutral ceramidase, both in cell lysates and in intact cells. A second generation of substrates, incorporating the natural 2-(N-acylamino)-1,3-diol-4-ene framework (compounds RBM15) is also reported. Among them, the corresponding fatty acyl amides with an unsaturated N-acyl chain can be used as substrates to determine alkaline ceramidase (ACER)1 and ACER2 activities. In particular, compound RBM15C18:1 has emerged as the best fluorogenic probe reported so far to measure ACER1 and ACER2 activities in a 96-well plate format.

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Section: Discussionsupporting

confidence: 88%

New fluorogenic probes for neutral and alkaline ceramidases

Casasampere

Bielsa

Riba

et al. 2019

Journal of Lipid Research

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“…After analyzing aCDase deficiency, we investigated effects of increasing sphingolipid content during HSV-1 infection. From literature it is known that aCDase is usually active in lysosomes and MVBs [29][30][31]37 . To test whether aCDase directly interacts with HSV-1, we infected macrophages with HSV-1 and stained for aCDase and HSV-1 after 30 min.…”

Section: Resultsmentioning

confidence: 99%

Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease

et al. 2020

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Macrophages have important protective functions during infection with herpes simplex virus type 1 (HSV-1). However, molecular mechanisms that restrict viral propagation and protect from severe disease are unclear. Here we show that macrophages take up HSV-1 via endocytosis and transport the virions into multivesicular bodies (MVBs). In MVBs, acid ceramidase (aCDase) converts ceramide into sphingosine and increases the formation of sphingosine-rich intraluminal vesicles (ILVs). Once HSV-1 particles reach MVBs, sphingosine-rich ILVs bind to HSV-1 particles, which restricts fusion with the limiting endosomal membrane and prevents cellular infection. Lack of aCDase in macrophage cultures or in Asah1 −/− mice results in replication of HSV-1 and Asah1 −/− mice die soon after systemic or intravaginal inoculation. The treatment of macrophages with sphingosine enhancing compounds blocks HSV-1 propagation, suggesting a therapeutic potential of this pathway. In conclusion, aCDase loads ILVs with sphingosine, which prevents HSV-1 capsids from penetrating into the cytosol.

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“…To investigate the underlying mechanism of this lipid switch, we inspected the UBTD1 potential partners and identified ASAH1. ASAH1 is synthesized in the ER as an inactive proenzyme and must be activated through autocleavage to become active in the lysosome [28,29]. This process is fundamental since ASAH1 is prominently involved in a genetic lysosomal storage disorder in human (Farber's disease) [30].…”

Section: Discussionmentioning

confidence: 99%

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling

Torrino

Tiroille

Dolfi

et al. 2020

Preprint

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To adapt in an ever-changing environment, cells must integrate physical and chemical signals and translate them into biological meaningful information through complex signaling pathways. By combining lipidomic and proteomic approaches with functional analysis, we have shown that UBTD1 (Ubiquitin domain-containing protein 1) plays a crucial role in both the EGFR (Epidermal Growth Factor Receptor) self-phosphorylation and its lysosomal degradation. On the one hand, by modulating the cellular level of ceramides through ASAH1 (N-Acylsphingosine Amidohydrolase 1) ubiquitination, UBTD1 controls the ligand-independent phosphorylation of EGFR. On the other hand, UBTD1, via the ubiquitination of SQSTM1/p62 (Sequestosome 1) and endolysosome positioning, participates in the lysosomal degradation of EGFR. The coordination of these two ubiquitin-dependent processes contributes to the control of the duration of the EGFR signal. Moreover, we showed that UBTD1 depletion exacerbates EGFR signaling and induces cell proliferation emphasizing a hitherto unknown function of UBTD1 in EGF-driven cell proliferation. IntroductionAll living organisms perceive variations in their environment and translate them into intracellular signals via signaling pathways. In multicellular organisms, disturbances in this signal transduction mechanism induce inappropriate cell behavior and are associated with a plethora of diseases including cancer. Cellular signaling can be viewed as a finely tuned "space-time continuum" [1]. Receptors activated by their ligands at the plasma membrane are endocytosed, then moved along endocytic compartments to be routed to the lysosomes for final degradation or recycled back to the cell surface. Thus, the signal delivered to the cell is the sum of the signals emitted by the activated receptor at the plasma membrane and during its intracellular trafficking [2]. The responsiveness of these processes requires fast and accurate control in space and time, which is mainly ensured by post-translational modification (PTM) of proteins. Broadly, several aspects of cell signaling and receptor trafficking are regulated by proteolytic or non-proteolytic ubiquitination [2-6].Protein ubiquitination is a PTM that results in the covalent attachment of one or more ubiquitin to lysine residues of the substrate [7][8][9]. Ubiquitin conjugation occurs in a sequential three-step enzymatic process involving E1 (ubiquitin activation), E2 (ubiquitin conjugation), and E3 (ubiquitin ligation). In this hierarchical framework, there are only two E1s, over 30 E2s and hundreds of E3s in human, illustrating the large spectrum of E2s that contrasts with the high specificity of E3s in the recognition of substrates [10,11]. While the interaction of E3s with their substrates confers specificity to the system, E2s are more versatile and are commonly considered as "ubiquitin carriers" with an auxiliary rather than control role.However, the modulation of the functionality of E2/E3 complexes by scaffold proteins has been poorly investigated and few proteins ...

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Structural basis for the activation of acid ceramidase

Cited by 76 publications

References 74 publications

New fluorogenic probes for neutral and alkaline ceramidases

New fluorogenic probes for neutral and alkaline ceramidases

Acid ceramidase of macrophages traps herpes simplex virus in multivesicular bodies and protects from severe disease

UBTD1 regulates ceramide balance and endolysosomal positioning to coordinate EGFR signaling

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