IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity

Gómez-Herranz, Maria; Taylor, Jordan S.; Sloan, Richard D.

doi:10.1016/j.jbc.2022.102741

Cited by 55 publications

(42 citation statements)

References 164 publications

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“…We observed that the functions of many retrieved proteins with reduced Nt-acetylation in Naa20 -/- MEFs were apoptosis-related ( Supplementary Dataset 1 and Table 1 ). Among them, we found TMEM258, a central mediator of ER quality control via apoptosis 33 ; importin 7, which is involved via the Hippo pathway in the expression of genes important in apoptosis 34 ; and IFM3, a member of the Interferon-induced transmembrane proteins (IFITMs) family 35 . This intriguing observation led us to note that procaspases-3, -8, -9, BAX, APAF1, and BID, which are major contributors to extrinsic and intrinsic apoptosis ( Supplementary Fig.1), systematically displayed Asp or Glu at position 2.…”

Section: Resultsmentioning

confidence: 99%

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

Guedes,

Boyer,

Elurbide

et al. 2023

Preprint

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N-terminal acetyltransferase B (NatB) is a major contributor to the N-terminal acetylome and is implicated in several key cellular processes including apoptosis and proteostasis. However, the molecular mechanisms linking NatB-mediated N-terminal acetylation to apoptosis and its relationship with protein homeostasis remain elusive. In this study, we generated mouse embryonic fibroblasts (MEFs) with an inactivated catalytic subunit of NatB (Naa20-/-) to investigate the impact of NatB deficiency on apoptosis regulation. Through quantitative N-terminomics, label-free quantification, and targeted proteomics, we demonstrated that NatB does not influence the proteostasis of all its substrates. Instead, our focus on putative NatB-dependent apoptotic factors revealed that NatB-mediated acetylation serves as a protective shield against UBR4 and UBR1 Arg/N-recognin-mediated degradation. Notably,Naa20-/-MEFs exhibited reduced responsiveness to extrinsic pro-apoptotic stimuli, a phenotype that was partially reversible upon UBR4 Arg/N-recognin silencing and consequent inhibition of procaspase-8 degradation. Collectively, our results shed light on how the interplay between NatB-mediated acetylation and the Arg/N-degron pathway impacts apoptosis regulation, providing new perspectives in the field including in therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

Guedes,

Boyer,

Elurbide

et al. 2023

Preprint

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“…IFITM3 was upregulated in RUNX1- deficient HEL cells and primary MK (Figures 6E and 7C) but IFITM3 knockdown did not inhibit fibrinogen uptake (Figure S2) suggesting that in these cells it may not IFITM3-driven. IFITM3 effect see in sepsis 40 may require other interferon-induced genes as well 44,45 .…”

Section: Discussionmentioning

confidence: 99%

“…IFITMs are important effectors in innate immunity and cancer biology 44,45 and RUNX1 is a negative regulator of neutrophil cytokine production 56,57 . The IFITM3 upregulation in RUNX1 -deficient HEL cells and MK (Figures 6 and 7) is novel and maybe relevant to autoimmune manifestations 12,58 and leukemic predisposition of FPDMM.…”

Section: Discussionmentioning

confidence: 99%

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Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

Carpio-Cano,

Mao,

Goldfinger

et al. 2023

Preprint

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Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germline RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMM), is associated with thrombocytopenia, platelet dysfunction and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen and IgG levels were decreased in a FPDMM patient. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, siRNA RUNX1 knockdown (KD) increased uptake of these proteins over 24 hours compared to control cells, with increases in caveolin-1 and flotillin-1 (two independent regulators of clathrin-independent endocytosis), LAMP2 (a lysosomal marker), RAB11 (a marker of recycling endosomes) and IFITM3. Caveolin-1 downregulation in RUNX1-deficient HEL cells abrogated the increased uptake of albumin, but not fibrinogen. Albumin, but not fibrinogen, partially colocalized with caveolin-1. RUNX1 knockdown increased colocalization of albumin with flotillin and of fibrinogen with RAB11 suggesting altered trafficking of both. The increased albumin and fibrinogen uptake and levels of caveolin-1, flotillin-1, LAMP2 and IFITM3 were recapitulated by shRNA RUNX1 knockdown in CD34+-derived MK. These studies provide the first evidence that in RUNX1-haplodeficiency platelet endocytosis of albumin and fibrinogen is impaired and that megakaryocytes have enhanced endocytosis with defective trafficking leading to loss of these proteins by distinct mechanisms. They provide new insights into mechanisms governing endocytosis and α-granule deficiencies in RUNX1-haplodeficiency.

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“…Among these ISGs, interferon inducible transmembrane protein (IFITM) proteins are a class of cellular restriction factors targeting the entry step of multiple enveloped viruses, including influenza A virus (IAV)., 14,15 flaviviruses (such as West Nile virus 16 and Zika virus 17 ), filoviruses (Ebola virus 18 ), bunyaviruses (Rift valley fever virus, RVFV 19 ), rotavirus, 20 and vaccinia virus 21 . Previous study showed that mice lacking IFTIM3 are more susceptible to infection by IAV, West Nile Virus, and a range of alphaviruses 22 . Our group have demonstrated that African Green Monkey IFITM3 could inhibit SFTSV replication 23 .…”

Section: Introductionmentioning

confidence: 99%

IFITM3 inhibits severe fever with thrombocytopenia syndrome virus entry and interacts with viral Gc protein

Du,

Wang,

Wang

et al. 2024

Journal of Medical Virology

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Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick‐borne hemorrhagic fever disease with high fatality rate of 10%–20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad‐spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti‐SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti‐SFTSV function by blocking Gn/Gc‐mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3‐Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3‐Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs‐mediated anti‐SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.

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IFITM proteins: Understanding their diverse roles in viral infection, cancer, and immunity

Cited by 55 publications

References 164 publications

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

NatB-dependent acetylation protects procaspase-8 from UBR4-mediated degradation and is required for full induction of the extrinsic apoptosis pathway

Altered Platelet-Megakaryocyte Endocytosis and Trafficking of Albumin and Fibrinogen inRUNX1Haplodeficiency

IFITM3 inhibits severe fever with thrombocytopenia syndrome virus entry and interacts with viral Gc protein

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