bims-minimp 2022-01-30 papers

on Mitochondria, innate immunity, proteostasis

Issue of 2022–01–30
ten papers selected by
Hanna Salmonowicz, International Institute of Molecular Mechanisms and Machines of the Polish Academy of Sciences

Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a novel complex III specific assembly factor in mitochondria.
Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth.
Coordinated Translocation of Presequence-Containing Precursor Proteins Across Two Mitochondrial Membranes: Knowns and Unknowns of How TOM and TIM23 Complexes Cooperate With Each Other.
Targeting the immune system toward novel therapeutic avenues to fight brain aging and neurodegeneration.
The transmembrane endoplasmic reticulum-associated E3 ubiquitin ligase TRIM13 restrains the pathogenic-DNA-triggered inflammatory response.
Selective autophagy controls innate immune response through a TAK1/TAB2/SH3PX1 axis.
Sex- and strain-specific effects of mitochondrial uncoupling on age-related metabolic diseases in high-fat diet-fed mice.
Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation.
TDRD3 is an antiviral restriction factor that promotes IFN signaling with G3BP1.
Eukaryotic lipid droplets: metabolic hubs, and immune first responders.

Mol Biol Cell. 2022 Jan 26. mbcE21030143

Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a novel complex III specific assembly factor in mitochondria.

Katarzyna Justyna Chojnacka, Praveenraj Elancheliyan, Ben Hur Marins Mussulini, Karthik Mohanraj, Sylvie Callegari, Aleksandra Gosk, Tomasz Banach, Tomasz Góral, Karolina Szczepanowska, Peter Rehling, Remigiusz Adam Serwa, Agnieszka Chacińska.

Assembly of the dimeric complex III (CIII2) in the mitochondrial inner membrane is an intricate process, in which several accessory proteins are involved as assembly factors. Despite numerous studies, this process is yet to be fully understood. Here we report the identification of human OCIAD2 (Ovarian Carcinoma Immunoreactive Antigen domain containing protein 2) protein as an assembly factor for CIII2. OCIAD2 was found deregulated in several carcinomas and also in some neurogenerative disorders, however its non-pathological role had not been elucidated. We have shown that OCIAD2 localizes to mitochondria and interacts with electron transport chain (ETC) proteins. Complete loss of OCIAD2 using gene editing in HEK293 cells resulted in abnormal mitochondrial morphology, a substantial decrease of both CIII2 and supercomplex III2+IV, and reduction in CIII enzymatic activity. Identification of OCIAD2 as a protein required for assembly of functional CIII2 provides a new insight into the biogenesis and architecture of the ETC. Elucidating the mechanism of OCIAD2 action is important both for the understanding of cellular metabolism and for an understanding of its role in malignant transformation.

DOI: https://doi.org/10.1091/mbc.E21-03-0143
Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01805-2. [Epub ahead of print]38(4): 110290

Dual role of Mic10 in mitochondrial cristae organization and ATP synthase-linked metabolic adaptation and respiratory growth.

Heike Rampelt, Florian Wollweber, Mariya Licheva, Rinse de Boer, Inge Perschil, Liesa Steidle, Thomas Becker, Maria Bohnert, Ida van der Klei, Claudine Kraft, Martin van der Laan, Nikolaus Pfanner.

  Invaginations of the mitochondrial inner membrane, termed cristae, are hubs for oxidative phosphorylation. The mitochondrial contact site and cristae organizing system (MICOS) and the dimeric F1Fo-ATP synthase play important roles in controlling cristae architecture. A fraction of the MICOS core subunit Mic10 is found in association with the ATP synthase, yet it is unknown whether this interaction is of relevance for mitochondrial or cellular functions. Here, we established conditions to selectively study the role of Mic10 at the ATP synthase. Mic10 variants impaired in MICOS functions stimulate ATP synthase oligomerization like wild-type Mic10 and promote efficient inner membrane energization, adaptation to non-fermentable carbon sources, and respiratory growth. Mic10's functions in respiratory growth largely depend on Mic10ATPsynthase, not on Mic10MICOS. We conclude that Mic10 plays a dual role as core subunit of MICOS and as partner of the F1Fo-ATP synthase, serving distinct functions in cristae shaping and respiratory adaptation and growth.

Keywords:  ATP synthase; MICOS; Mic10; cristae organization; inner membrane; membrane architecture; membrane potential; metabolic adaptation; mitochondria; respiration

DOI:  https://doi.org/10.1016/j.celrep.2021.110290
Front Physiol. 2021 ;12 806426

Coordinated Translocation of Presequence-Containing Precursor Proteins Across Two Mitochondrial Membranes: Knowns and Unknowns of How TOM and TIM23 Complexes Cooperate With Each Other.

Marcel G Genge, Dejana Mokranjac.

  The vast majority of mitochondrial proteins are encoded in the nuclear genome and synthesized on cytosolic ribosomes as precursor proteins with specific mitochondrial targeting signals. Mitochondrial targeting signals are very diverse, however, about 70% of mitochondrial proteins carry cleavable, N-terminal extensions called presequences. These amphipathic helices with one positively charged and one hydrophobic surface target proteins to the mitochondrial matrix with the help of the TOM and TIM23 complexes in the outer and inner membranes, respectively. Translocation of proteins across the two mitochondrial membranes does not take place independently of each other. Rather, in the intermembrane space, where the two complexes meet, components of the TOM and TIM23 complexes form an intricate network of protein-protein interactions that mediates initially transfer of presequences and then of the entire precursor proteins from the outer to the inner mitochondrial membrane. In this Mini Review, we summarize our current understanding of how the TOM and TIM23 complexes cooperate with each other and highlight some of the future challenges and unresolved questions in the field.

Keywords:  TIM23 complex; TOM complex; TOM-TIM23 contacts; intermembrane space; mitochondria; precursor transfer; presequence pathway; protein translocation

DOI:  https://doi.org/10.3389/fphys.2021.806426
Eur J Neurosci. 2022 Jan 24.

Targeting the immune system toward novel therapeutic avenues to fight brain aging and neurodegeneration.

Javier María Peralta Ramos, Denise Kviatcovsky, Michal Schwartz.

  The incidence of age-related dementia is growing with increased longevity, yet there are currently no disease-modifying therapies for these devastating disorders. Studies over the last several years have led to an evolving awareness of the role of the immune system in supporting brain maintenance and repair, displaying a diverse repertoire of functions while orchestrating the crosstalk between the periphery and the brain. Here, we provide insights into the current understanding of therapeutic targets that could be adopted to modulate the immune system, either systemically or locally, to defeat brain aging and neurodegeneration.

Keywords:  Aging; Neurodegeneration; Therapeutic targets

DOI:  https://doi.org/10.1111/ejn.15609
Sci Adv. 2022 Jan 28. 8(4): eabh0496

The transmembrane endoplasmic reticulum-associated E3 ubiquitin ligase TRIM13 restrains the pathogenic-DNA-triggered inflammatory response.

Xuelian Li, Zhou Yu, Qian Fang, Mingjin Yang, Jiaying Huang, Zheng Li, Jianli Wang, Taoyong Chen.

The endoplasmic reticulum (ER)-localized stimulator of interferon genes (STING) is the core adaptor for the pathogenic-DNA-triggered innate response. Aberrant activation of STING causes autoinflammatory and autoimmune diseases, raising the concern about how STING is finely tuned during innate response to pathogenic DNAs. Here, we report that the transmembrane domain (TM)-containing ER-localized E3 ubiquitin ligase TRIM13 (tripartite motif containing 13) is required for restraining inflammatory response to pathogenic DNAs. TRIM13 deficiency enhances pathogenic-DNA-triggered inflammatory cytokine production, inhibits DNA virus replication, and causes age-related autoinflammation. Mechanistically, TRIM13 interacts with STING via the TM and catalyzes Lys6-linked polyubiquitination of STING, leading to decelerated ER exit and accelerated ER-initiated degradation of STING. STING deficiency reverses the enhanced innate anti-DNA virus response in TRIM13 knockout mice. Our study delineates a potential strategy for controlling the homeostasis of STING by transmembrane ER-associated TRIM13 during the pathogenic-DNA-triggered inflammatory response.

DOI: https://doi.org/10.1126/sciadv.abh0496
Cell Rep. 2022 Jan 25. pii: S2211-1247(21)01801-5. [Epub ahead of print]38(4): 110286

Selective autophagy controls innate immune response through a TAK1/TAB2/SH3PX1 axis.

Panagiotis Tsapras, Stavroula Petridi, Selina Chan, Marta Geborys, Anne-Claire Jacomin, Antonia P Sagona, Pascal Meier, Ioannis P Nezis.

  Selective autophagy is a catabolic route that turns over specific cellular material for degradation by lysosomes, and whose role in the regulation of innate immunity is largely unexplored. Here, we show that the apical kinase of the Drosophila immune deficiency (IMD) pathway Tak1, as well as its co-activator Tab2, are both selective autophagy substrates that interact with the autophagy protein Atg8a. We also present a role for the Atg8a-interacting protein Sh3px1 in the downregulation of the IMD pathway, by facilitating targeting of the Tak1/Tab2 complex to the autophagy platform through its interaction with Tab2. Our findings show the Tak1/Tab2/Sh3px1 interactions with Atg8a mediate the removal of the Tak1/Tab2 signaling complex by selective autophagy. This in turn prevents constitutive activation of the IMD pathway in Drosophila. This study provides mechanistic insight on the regulation of innate immune responses by selective autophagy.

Keywords:  Drosophila; IMD; Sh3px1; Tab2; Tak1; autophagy; chronic inflammation; innate immunity

DOI:  https://doi.org/10.1016/j.celrep.2021.110286
Aging Cell. 2022 Jan 28. e13539

Sex- and strain-specific effects of mitochondrial uncoupling on age-related metabolic diseases in high-fat diet-fed mice.

Leigh Goedeke, Kelsey N Murt, Andrea Di Francesco, João Paulo Camporez, Ali R Nasiri, Yongliang Wang, Xian-Man Zhang, Gary W Cline, Rafael de Cabo, Gerald I Shulman.

  Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria and may have evolved to protect cells against the production of damaging reactive oxygen species. Therefore, compounds that enhance mitochondrial uncoupling are potentially attractive anti-aging therapies; however, chronic ingestion is associated with a number of unwanted side effects. We have previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-directed and promotes oxidation of hepatic triglycerides by causing a subtle sustained increase in hepatic mitochondrial inefficiency. Here, we sought to leverage the higher therapeutic index of CRMP to test whether mild mitochondrial uncoupling in a liver-directed fashion could reduce oxidative damage and improve age-related metabolic disease and lifespan in diet-induced obese mice. Oral administration of CRMP (20 mg/[kg-day] × 4 weeks) reduced hepatic lipid content, protein kinase C epsilon activation, and hepatic insulin resistance in aged (74-week-old) high-fat diet (HFD)-fed C57BL/6J male mice, independently of changes in body weight, whole-body energy expenditure, food intake, or markers of hepatic mitochondrial biogenesis. CRMP treatment was also associated with a significant reduction in hepatic lipid peroxidation, protein carbonylation, and inflammation. Importantly, long-term (49 weeks) hepatic mitochondrial uncoupling initiated late in life (94-104 weeks), in conjugation with HFD feeding, protected mice against neoplastic disorders, including hepatocellular carcinoma (HCC), in a strain and sex-specific manner. Taken together, these studies illustrate the complex variation of aging and provide important proof-of-concept data to support further studies investigating the use of liver-directed mitochondrial uncouplers to promote healthy aging in humans.

Keywords:  2,4-dinitrophenol; anti-aging; hepatic steatosis; insulin sensitivity; longevity; mitochondrial uncoupling

DOI:  https://doi.org/10.1111/acel.13539
Cell Death Differ. 2022 Jan 22.

Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation.

Lingli Zhou, Xing He, Liqiu Wang, Ping Wei, Zhe Cai, Song Zhang, Shouheng Jin, Huasong Zeng, Jun Cui.

The nucleotide-binding oligomerization domain protein 2 (NOD2) senses bacterial peptidoglycan to induce proinflammatory and antimicrobial responses. Dysregulation of NOD2 signaling is involved in multiple inflammatory disorders. Recently, S-palmitoylation, a novel type of post-translational modification, is reported to play a crucial role in membrane association and ligand-induced signaling of NOD2, yet its influence on the stability of NOD2 is unclear. Here we show that inhibition of S-palmitoylation facilitates the SQSTM1/p62-mediated autophagic degradation of NOD2, while S-palmitoylation of NOD2 by ZDHHC5 promotes the stability of NOD2. Furthermore, we identify a gain-of-function R444C variant of NOD2 short isoform (NOD2s-R444C) in autoinflammatory disease, which induces excessive inflammation through its high S-palmitoylation level. Mechanistically, the NOD2s-R444C variant possesses a stronger binding ability to ZDHHC5, which promotes its S-palmitoylation, and restricts its autophagic degradation by reducing its interaction with SQSTM1/p62. Taken together, our study reveals the regulatory role of S-palmitoylation in controlling NOD2 stability through the crosstalk with autophagy, and provides insights into the association between dysfunctional S-palmitoylation and the occurrence of inflammatory diseases.

DOI: https://doi.org/10.1038/s41418-022-00942-z
PLoS Pathog. 2022 Jan 27. 18(1): e1010249

TDRD3 is an antiviral restriction factor that promotes IFN signaling with G3BP1.

Matthew Deater, Manasi Tamhankar, Richard E Lloyd.

Stress granules (SGs) are highly dynamic cytoplasmic foci that form in response to activation of the integrated stress response (ISR) that results in eIF2α phosphorylation and global translation shutdown. Stress granules, which are largely nucleated by G3BP1, serve as hubs for mRNA triage, but there is mounting evidence that they also perform cell signaling functions that are vital to cell survival, particularly during viral infection. We previously showed that SG formation leads to NFκB activation and JNK signaling and that this association may be due in part to G3BP1-dependent recruitment of PKR to SGs. Others have reported close associations between G3BP1 and various innate immune PRRs of the type 1 interferon signaling system, including RIG-I. We also reported SG assembly dynamics is dependent on the arginine-methylation status of G3BP1. Another protein that rapidly localizes to SGs, TDRD3, is a methyl reader protein that performs transcriptional activation and adaptor functions within the nucleus, but neither the mechanism nor its function in SGs is clear. Here, we present evidence that TDRD3 localizes to SGs partly based upon methylation potential of G3BP1. We also characterize granules that TDRD3 forms during overexpression and show that these granules can form in the absence of G3BP but also contain translation components found in canonical SGs. We also show for the first time that SGs recruit additional interferon effectors IRF3, IRF7, TBK1, and Sting, and provide evidence that TDRD3 may play a role in recruitment of these factors. We also present evidence that TDRD3 is a novel antiviral protein that is cleaved by enteroviral 2A proteinase. G3BP1 and TDRD3 knockdown in cells results in altered transcriptional regulation of numerous IFN effectors in complex modulatory patterns that are distinctive for G3BP1 and TDRD3. Overall, we describe a novel role of TDRD3 in innate immunity in which G3BP1 and TDRD3 may coordinate to play important roles in regulation of innate antiviral defenses.

DOI: https://doi.org/10.1371/journal.ppat.1010249
Trends Endocrinol Metab. 2022 Jan 19. pii: S1043-2760(21)00301-5. [Epub ahead of print]

Eukaryotic lipid droplets: metabolic hubs, and immune first responders.

Marta Bosch, Albert Pol.

  As major eukaryotic lipid storage organelles, lipid droplets (LDs) are metabolic hubs coordinating energy flux and building block distribution. Infectious pathogens often promote accumulation and physically interact with LDs. The most accepted view is that host LDs are hijacked by invaders to draw on nutrients for host colonisation. However, unique traits such as biogenesis plasticity, dynamic proteome, signalling capacity, and ability to interact with other organelles endow LDs with competencies to face complex biological challenges. Here, we focus on published data suggesting that LDs are not usurped organelles but innate immunity first responders. By comparison with analogous mechanisms activated on LDs in nutrient-poor environments, our review supports the hypothesis that host LDs actively participate in immunometabolism, immune signalling, and microbial killing.

Keywords:  infection; innate immunity; lipid droplet; metabolism

DOI:  https://doi.org/10.1016/j.tem.2021.12.006