PMID- 36453897
OWN - NLM
STAT- MEDLINE
DCOM- 20230106
LR  - 20231020
IS  - 2165-0497 (Electronic)
IS  - 2165-0497 (Linking)
VI  - 10
IP  - 6
DP  - 2022 Dec 21
TI  - ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
PG  - e0389322
LID - 10.1128/spectrum.03893-22 [doi]
LID - e03893-22
AB  - Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that 
      binds to target proteins in a process termed ISGylation. ISG15, first described 
      as an antiviral molecule against many viruses, participates in numerous cellular 
      processes, from immune modulation to the regulation of genome stability. 
      Interestingly, the role of ISG15 as a regulator of cell metabolism has recently 
      gained strength. We previously described ISG15 as a regulator of mitochondrial 
      functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia 
      virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid 
      metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV 
      infection on lipid metabolism. We show that Isg15(-/-) BMDMs demonstrate 
      alterations in the levels of several key proteins of lipid metabolism that result 
      in differences in the lipid profile compared with Isg15(+/+) (wild-type [WT]) 
      BMDMs. Specifically, Isg15(-/-) BMDMs present reduced levels of neutral lipids, 
      reflected by decreased lipid droplet number. These alterations are linked to 
      increased levels of lipases and are independent of enhanced fatty acid oxidation 
      (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes 
      of BMDMs and alterations in the lipid content of these cells, which appear 
      exacerbated in Isg15(-/-) BMDMs. Such metabolic changes are likely caused by 
      increased expression of the metabolic regulators peroxisome 
      proliferator-activated receptor-gamma (PPARgamma) and PPARgamma coactivator-1alpha (PGC-1alpha). In 
      summary, our results highlight that ISG15 controls BMDM lipid metabolism during 
      viral infections, suggesting that ISG15 is an important host factor to restrain 
      VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are 
      continuously expanding, and growing evidence supports its role as a relevant 
      modulator of cell metabolism. In this work, we highlight how the absence of ISG15 
      impacts macrophage lipid metabolism in the context of viral infections and how 
      poxviruses modulate metabolism to ensure successful replication. Our results open 
      the door to new advances in the comprehension of macrophage immunometabolism and 
      the interaction between VACV and the host.
FAU - Albert, Manuel
AU  - Albert M
AUID- ORCID: 0000-0001-9774-3668
AD  - Department of Preventive Medicine, Public Health and Microbiology, Universidad 
      Autonoma de Madrid, Madrid, Spain.
FAU - Vazquez, Jesus
AU  - Vazquez J
AD  - Centro Nacional de Investigaciones Cardiovasculares (CNIC-ISCIII), Madrid, Spain.
FAU - Falcon-Perez, Juan M
AU  - Falcon-Perez JM
AD  - CIC-bioGUNE-Centro de Investigacion Cooperativa en Biociencias, Vizcaya, Spain.
FAU - Balboa, Maria A
AU  - Balboa MA
AD  - Consejo Superior de Investigaciones Cientificas (CSIC), Instituto de Biologia y 
      Genetica Molecular, Valladolid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Liesa, Marc
AU  - Liesa M
AD  - Department of Medicine, Endocrinology, David Geffen School of Medicine at UCLA, 
      Los Angeles, California, USA.
AD  - Institut de Biologia Molecular de Barcelona, IBMB, CSIC, Barcelona, Spain.
FAU - Balsinde, Jesus
AU  - Balsinde J
AD  - Consejo Superior de Investigaciones Cientificas (CSIC), Instituto de Biologia y 
      Genetica Molecular, Valladolid, Spain.
AD  - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas 
      Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
FAU - Guerra, Susana
AU  - Guerra S
AUID- ORCID: 0000-0001-9067-2991
AD  - Department of Preventive Medicine, Public Health and Microbiology, Universidad 
      Autonoma de Madrid, Madrid, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221201
PL  - United States
TA  - Microbiol Spectr
JT  - Microbiology spectrum
JID - 101634614
RN  - 0 (Cytokines)
RN  - 9008-11-1 (Interferons)
RN  - 0 (Lipids)
RN  - 0 (PPAR gamma)
RN  - 0 (Ubiquitins)
SB  - IM
MH  - *Cytokines/metabolism
MH  - Interferons
MH  - *Lipid Metabolism
MH  - Lipids
MH  - PPAR gamma/metabolism
MH  - *Ubiquitins/genetics/metabolism
MH  - *Vaccinia/genetics/metabolism
MH  - Vaccinia virus/genetics
MH  - Animals
PMC - PMC9769738
OTO - NOTNLM
OT  - host-pathogen interactions
OT  - innate immunity
OT  - interferons
COIS- The authors declare no conflict of interest.
EDAT- 2022/12/02 06:00
MHDA- 2022/12/28 06:00
PMCR- 2022/12/01
CRDT- 2022/12/01 09:04
PHST- 2022/12/02 06:00 [pubmed]
PHST- 2022/12/28 06:00 [medline]
PHST- 2022/12/01 09:04 [entrez]
PHST- 2022/12/01 00:00 [pmc-release]
AID - 03893-22 [pii]
AID - spectrum.03893-22 [pii]
AID - 10.1128/spectrum.03893-22 [doi]
PST - ppublish
SO  - Microbiol Spectr. 2022 Dec 21;10(6):e0389322. doi: 10.1128/spectrum.03893-22. 
      Epub 2022 Dec 1.