Thaddaeus Mutugi Nthiga

• Slinning, Malene Skuseth; Nthiga, Thaddaeus Mutugi; Eichner, Christiane; Khadija, Syeda; Rome, Leonard H. & Nilsen, Frank [Vis alle 7 forfattere av denne artikkelen] (2024). Major vault protein is partof an extracellular cement materialin the Atlantic salmon louse(Lepeophtheirus salmonis). Scientific Reports. 14. doi: 10.1038/s41598-024-65683-0. Fulltekst i vitenarkiv Vis sammendrag

  Major vault protein (MVP) is the main component of the vault complex, which is a highly conserved ribonucleoprotein complex found in most eukaryotic organisms. MVP or vaults have previously been found to be overexpressed in multidrug-resistant cancer cells and implicated in various cellular processes such as cell signaling and innate immunity. The precise function of MVP is, however, poorly understood and its expression and probable function in lower eukaryotes are not well characterized. In this study, we report that the Atlantic salmon louse expresses three full-length MVP paralogues (LsMVP1-3). Furthermore, we extended our search and identified MVP orthologues in several other ecdysozoan species. LsMVPs were shown to be expressed in various tissues at both transcript and protein levels. In addition, evidence for LsMVP to assemble into vaults was demonstrated by performing differential centrifugation. LsMVP was found to be highly expressed in cement, an extracellular material produced by a pair of cement glands in the adult female salmon louse. Cement is important for the formation of egg strings that serve as protective coats for developing embryos. Our results imply a possible novel function of LsMVP as a secretory cement protein. LsMVP may play a role in structural or reproductive functions, although this has to be further investigated.

• Nthiga, Thaddaeus Mutugi; Shrestha, Birendra Kumar; Bruun, Jack-Ansgar; Larsen, Kenneth Bowitz; Lamark, Trond & Johansen, Terje (2021). Regulation of Golgi turnover by CALCOCO1-mediated selective autophagy. Journal of Cell Biology. ISSN 0021-9525. 220(6), s. e202006128–e202006128. doi: 10.1083/jcb.202006128. Fulltekst i vitenarkiv Vis sammendrag

  The Golgi complex is essential for the processing, sorting, and trafficking of newly synthesized proteins and lipids. Golgi turnover is regulated to meet different cellular physiological demands. The role of autophagy in the turnover of Golgi, however, has not been clarified. Here we show that CALCOCO1 binds the Golgi-resident palmitoyltransferase ZDHHC17 to facilitate Golgi degradation by autophagy during starvation. Depletion of CALCOCO1 in cells causes expansion of the Golgi and accumulation of its structural and membrane proteins. ZDHHC17 itself is degraded by autophagy together with other Golgi membrane proteins such as TMEM165. Taken together, our data suggest a model in which CALCOCO1 mediates selective Golgiphagy to control Golgi size and morphology in eukaryotic cells via its interaction with ZDHHC17.

• Nthiga, Thaddaeus Mutugi; Shrestha, Birendra Kumar; Lamark, Trond & Johansen, Terje (2021). The soluble reticulophagy receptor CALCOCO1 is also a Golgiphagy receptor. Autophagy. ISSN 1554-8627. 17(8), s. 2051–2052. doi: 10.1080/15548627.2021.1940610. Fulltekst i vitenarkiv Vis sammendrag

  Cellular stress response mechanisms typically increase organellar quantity and volume. To restore cellular homeostasis and organellar integrity, the surplus organelles are cleared by macroautophagy/autophagy, an intracellular process that shuttles cytoplasmic material to the lysosomes for degradation. The degradation is mediated by autophagy receptors that selectively link the degradable cargo to the autophagy machinery. Studies have identified receptors for the degradation of mitochondria, endoplasmic reticulum, lysosomes, and peroxisomes. The autophagic degradation of the Golgi, named Golgiphagy, however, has remained undefined. The Golgi is essential for the processing, sorting and trafficking of proteins and lipids in the secretory pathway. In a recent study, we identified CALCOCO1 as a Golgiphagy receptor in response to nutrient deprivation. CALCOCO1 interacts with Golgi membranes by binding to cytoplasmic Ankyrin repeat (AR) domains of Golgi resident ZDHHC17 and ZDHHC13 palmitoyltransferases (PATs) via a defined zDHHC-AR-binding motif (zDABM) to recruit autophagy machinery. Lack of CALCOCO1 in cells causes an impaired Golgiphagy and expansion of the Golgi.

• Bhujabal, Zambarlal Babanrao; Larsen, Kenneth Bowitz; Bruun, Jack-Ansgar; Johansen, Terje; Shrestha, Birendra Kumar & Lamark, Trond [Vis alle 8 forfattere av denne artikkelen] (2020). CALCOCO1 acts with VAMP‐associated proteins to mediate ER‐phagy | The EMBO Journal | Springer Nature Link. EMBO Journal. ISSN 0261-4189. doi: 10.15252/embj.2019103649. Fulltekst i vitenarkiv Vis sammendrag

  The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER‐phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER‐resident proteins have been identified as ER‐phagy receptors so far. In this study, we have identified CALCOCO1 as a novel ER‐phagy receptor for the degradation of the tubular ER in response to proteotoxic and nutrient stress. CALCOCO1 is a homomeric protein that binds directly to ATG8 proteins via LIR‐ and UDS‐interacting region (UIR) motifs acting co‐dependently. CALCOCO1‐mediated ER‐phagy requires interaction with VAMP‐associated proteins VAPA and VAPB on the ER membranes via a conserved FFAT‐like motif. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux. Unlike the other ER‐phagy receptors, CALCOCO1 is peripherally associated with the ER. Therefore, we define CALCOCO1 as a soluble ER‐phagy receptor. A specialized form of autophagy named ER‐phagy restores endoplasmic reticulum (ER) homeostasis in response to nutrient stress. ER‐associated protein CALCOCO1 is a soluble receptor for specific degradation of tubular ER membranes, modulating autophagy during proteotoxic and nutrient stress in mammalian cells. ER‐associated protein CALCOCO1 is a soluble receptor for specific degradation of tubular ER membranes, modulating autophagy during proteotoxic and nutrient stress in mammalian cells.

• Nthiga, Thaddaeu Mutugi; Shrestha, Birendra Kumar; Lamark, Trond & Johansen, Terje (2020). CALCOCO1 is a soluble reticulophagy receptor. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2020.1797289. Fulltekst i vitenarkiv Vis sammendrag

  The endoplasmic reticulum (ER) is the largest membrane-bound organelle in eukaryotic cells and plays critical roles in diverse processes in metabolism, signaling and intracellular organization. In response to stress stimuli such as nutrient deprivation, accumulation of misfolded proteins or exposure to chemicals, the ER increases in size through upregulated synthesis of its components to counteract the stress. To restore physiological size, the excess ER components are continuously dismantled and degraded by reticulophagy, a form of autophagy that targets, via adaptor molecules called reticulophagy receptors, specific ER portions to the lysosome for degradation. Previous studies have identified several ER resident proteins as reticulophagy receptors. In a recent study, we identified CALCOCO1 as a soluble reticulophagy receptor for the degradation of tubular ER in response to proteotoxic and starvation-induced stress. On the ER membrane, CALCOCO1 interacts with VAPA and VAPB via a FFAT-like motif and recruits autophagy machinery by binding directly to Atg8-family proteins via LIR and UDS interacting region (UIR) motifs acting co-dependently. Depletion of CALCOCO1 in cultured cells led to an impaired ER degradation during stress.

• Nthiga, Thaddaeus Mutugi; Shrestha, Birendra Kumar; Sjøttem, Eva; Lamark, Trond & Johansen, Terje (2020). CALCOCO1 acts with VAMP ‐associated proteins to mediate ER ‐phagy. EMBO Journal. ISSN 0261-4189. doi: 10.15252/embj.2019103649. Fulltekst i vitenarkiv Vis sammendrag

  The endoplasmic reticulum (ER) plays important roles in protein synthesis and folding, and calcium storage. The volume of the ER and expression of its resident proteins are increased in response to nutrient stress. ER‐phagy, a selective form of autophagy, is involved in the degradation of the excess components of the ER to restore homeostasis. Six ER‐resident proteins have been identified as ER‐phagy receptors so far. In this study, we have identified CALCOCO1 as a novel ER‐phagy receptor for the degradation of the tubular ER in response to proteotoxic and nutrient stress. CALCOCO1 is a homomeric protein that binds directly to ATG8 proteins via LIR‐ and UDS‐interacting region (UIR) motifs acting co‐dependently. CALCOCO1‐mediated ER‐phagy requires interaction with VAMP‐associated proteins VAPA and VAPB on the ER membranes via a conserved FFAT‐like motif. Depletion of CALCOCO1 causes expansion of the ER and inefficient basal autophagy flux. Unlike the other ER‐phagy receptors, CALCOCO1 is peripherally associated with the ER. Therefore, we define CALCOCO1 as a soluble ER‐phagy receptor.

• Abudu, Yakubu Princely; Pankiv, Serhiy; Mathai, Benan John; Lystad, Alf Håkon; Bindesbøll, Christian & Brenne, Hanne Britt [Vis alle 14 forfattere av denne artikkelen] (2019). NIPSNAP1 and NIPSNAP2 act as “eat-me signal” for mitophagy. Developmental Cell. ISSN 1534-5807. 49(4), s. 509–525.e12. doi: 10.1016/j.devcel.2019.03.013. Fulltekst i vitenarkiv Vis sammendrag

  The clearance of damaged or dysfunctional mitochondria by selective autophagy (mitophagy) is important for cellular homeostasis and prevention of disease. Our understanding of the mitochondrial signals that trigger their recognition and targeting by mitophagy is limited. Here, we show that the mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) and NIPSNAP2 accumulate on the mitochondria surface upon mitochondrial depolarization. There, they recruit proteins involved in selective autophagy, including autophagy receptors and ATG8 proteins, thereby functioning as an “eat me” signal for mitophagy. NIPSNAP1 and NIPSNAP2 have a redundant function in mitophagy and are predominantly expressed in different tissues. Zebrafish lacking a functional Nipsnap1 display reduced mitophagy in the brain and parkinsonian phenotypes, including loss of tyrosine hydroxylase (Th1)-positive dopaminergic (DA) neurons, reduced motor activity, and increased oxidative stress.

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