Biology subjects

Jimenez-Morales, D.

Publications and source records attributed to Jimenez-Morales, D..

21 records · Page 2Linked to original sources

bioRxiv2020

Dynamic proteomics profiling of Legionella pneumophila infection unveils modulation of the host mitochondrial stress response pathway

The human pathogen Legionella pneumophila (L.p.) secretes ~330 bacterial effector proteins into the host cell which interfere with numerous cellular pathways and often regulate host cell proteins through post-translational modifications. However, the cellular targets and functions of most L.p. effectors are not known. In order to obtain a global overview of potential targets of these effectors, we analyzed the host cell proteome, ubiquitinome, and phosphoproteome during L.p. infection. Our analysis reveals dramatic spatiotemporal changes in the host cell proteome that are dependent on the secretion of bacterial effectors. Strikingly, we show that L.p. substantially reshapes the mitochondrial proteome and modulates mitochondrial stress response pathways such as the mitochondrial unfolded protein response (UPRmt). To our knowledge, this is the first evidence of manipulation of the UPRmt by a bacterial pathogen in mammalian cells. In addition, we have identified a previously uncharacterized L.p. effector that is targeted to host cell mitochondria and protects mitochondrial network integrity during mitochondrial stress.

cell biology↗

bioRxiv2019

Brown adipocyte NOSEMPE promotes nonmitochondrial thermogenesis and improves systemic metabolism through ATF4 activation

Mitochondrial transcription factor A (Tfam)-mediated mtDNA maintenance and transcription, as well as leucine-rich PPR motif-containing protein (Lrpprc)-mediated mtRNA maturation and translation are essential steps of mtDNA-encoded electron transport chain (ETC) protein expression. ETC is essential for mitochondrial thermogenesis, the process of oxygen-dependent heat production inside the mitochondria in brown adipocytes. Here we describe that Tfam or Lrpprc deficiency in brown adipocytes cause non-synchronized ETC mRNA and protein expression (NOSEMPE) and mitochondrial ETC imbalance, ultimately abolish mitochondrial thermogenesis. However, mice with NOSEMPE in brown adipocytes are cold resistant upon an acute 4{degrees}C cold challenge, because of augmented nonmitochondrial thermogenesis driven by the \"NOSEMPE[->]ATF4[->]proteome turnover\" pathway. Importantly, mice with either NOSEMPE or ATF4 overexpression in brown adipocytes are protected against high-fat-diet-induced metabolic abnormalities, indicating a positive association between nonmitochondrial thermogenesis in brown adipocytes and metabolic fitness. Thus, although brown adipocytes are defined by their unique ability to produce heat through mitochondrial respiration, our study demonstrates a novel cytosolic nonmitochondrial thermogenesis in brown adipocytes. Targeting this ATF4-dependent nonmitochondrial thermogenesis in brown adipocytes may represent a new therapeutic strategy for combating metabolic disorders.

physiology↗

bioRxiv2018

The cellular NMD pathway restricts Zika virus infection and is targeted by the viral capsid protein

Zika virus (ZIKV) infection of neural progenitor cells (NPCs) in utero is associated with neurological disorders, such as microcephaly1, but a detailed molecular understanding of ZIKV-induced pathogenesis is lacking. Here we show that in vitro ZIKV infection of human cells, including NPCs, causes disruption of the nonsense-mediated mRNA decay (NMD) pathway. NMD is a cellular mRNA surveillance mechanism that is required for normal brain size in mice2-4. Using affinity purification-mass spectrometry, we identified multiple cellular NMD factors that bind to the viral capsid protein, including the central NMD regulator up-frameshift protein 1 (UPF1)5. Endogenous UPF1 interacted with the viral capsid protein in co-immunoprecipitation experiments and capsid expression post-transcriptionally downregulated UPF1, a process that we confirmed occurs during de novo ZIKV infection. A further decrease in UPF1 levels by RNAi significantly enhanced ZIKV infection in NPC cultures. We therefore propose that ZIKV, via the capsid protein, has evolved a strategy to dampen antiviral activities of NMD6,7, which subsequently contributes to neuropathology in vivo.

microbiology↗