Kraft, C., Boya, P., Codogno, P., Elazar, Z., Eskelinen, E.-., Farrés, J., Kirkin, V., Jungbluth, H., Martinez, A., Pless, O., et al.
(2019). Driving next-generation autophagy researchers towards translation (DRIVE), an international PhD training program on autophagy. Autophagy,
The European autophagy consortium Driving next-generation autophagy researchers towards translation (DRIVE) held its kick-off meeting in Groningen on the 14th and 15th of June 2018. This Marie Skłodowska-Curie Early Training Network was approved under the European Union's Horizon 2020 Research and Innovation Program and is funded for 4 years. Within DRIVE, 14 European research teams from academia and industry will train 15 PhD students through applied, cross-disciplinary and collaborative macroautophagy/autophagy research. The goal of DRIVE is to stimulate applied approaches in autophagy research and provide training towards translation, while advancing our knowledge on autophagy in specific physiological and pathological states. The strong focus on translation will prepare the PhD students to be at the forefront to exploit autophagy for the development of therapies directly benefitting patients. Thereby, DRIVE will contribute to filling the educational gap that currently exists between academia and industry, and will prepare its PhD students for alternative and highly flexible professional paths..
(2019). History of the Selective Autophagy Research: How Did It Begin and Where Does It Stand Today?. Journal of molecular biology,
Kirkin, V. & Rogov, V.V.
(2019). A Diversity of Selective Autophagy Receptors Determines the Specificity of the Autophagy Pathway. Molecular cell,
Conway, O., Akpinar, H.A., Rogov, V. & Kirkin, V.
(2019). Selective autophagy receptors in neuronal health and disease. Journal of molecular biology,
Huber, J., Obata, M., Gruber, J., Akutsu, M., Löhr, F., Rogova, N., Güntert, P., Dikic, I., Kirkin, V., Komatsu, M., et al.
(2019). An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. Autophagy,
Short linear motifs, known as LC3-interacting regions (LIRs), interact with mactoautophagy/autophagy modifiers (Atg8/LC3/GABARAP proteins) via a conserved universal mechanism. Typically, this includes the occupancy of 2 hydrophobic pockets on the surface of Atg8-family proteins by 2 specific aromatic and hydrophobic residues within the LIR motifs. Here, we describe an alternative mechanism of Atg8-family protein interaction with the non-canonical UBA5 LIR, an E1-like enzyme of the ufmylation pathway that preferentially interacts with GABARAP but not LC3 proteins. By solving the structures of both GABARAP and GABARAPL2 in complex with the UBA5 LIR, we show that in addition to the binding to the 2 canonical hydrophobic pockets (HP1 and HP2), a conserved tryptophan residue N-terminal of the LIR core sequence binds into a novel hydrophobic pocket on the surface of GABARAP proteins, which we term HP0. This mode of action is unique for UBA5 and accompanied by large rearrangements of key residues including the side chains of the gate-keeping K46 and the adjacent K/R47 in GABARAP proteins. Swapping mutations in LC3B and GABARAPL2 revealed that K/R47 is the key residue in the specific binding of GABARAP proteins to UBA5, with synergetic contributions of the composition and dynamics of the loop L3. Finally, we elucidate the physiological relevance of the interaction and show that GABARAP proteins regulate the localization and function of UBA5 on the endoplasmic reticulum membrane in a lipidation-independent manner. Abbreviations: ATG: AuTophaGy-related; EGFP: enhanced green fluorescent protein; GABARAP: GABA-type A receptor-associated protein; ITC: isothermal titration calorimetry; KO: knockout; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NMR: nuclear magnetic resonance; RMSD: root-mean-square deviation of atomic positions; TKO: triple knockout; UBA5: ubiquitin like modifier activating enzyme 5..
Conway, O. & Kirkin, V.
(2017). Love laughs at Locksmiths: Ubiquitylation of p62 unlocks its autophagy receptor potential. Cell res,
The multimodular adapter p62/sequestosome-1 plays prominent roles in physiology and disease by mediating cell signaling and cargo degradation. The work by Peng et al. published recently in Cell Research provides mechanistic insights into activation of its autophagy receptor function critical for maintaining cell homeostasis during various forms of stress..
Bhujabal, Z., Birgisdottir, Å.B., Sjøttem, E., Brenne, H.B., Øvervatn, A., Habisov, S., Kirkin, V., Lamark, T. & Johansen, T.
(2017). FKBP8 recruits LC3A to mediate Parkin‐independent mitophagy. Embo reports,
Johansen, T., Birgisdottir, Å.B., Huber, J., Kniss, A., Dötsch, V., Kirkin, V. & Rogov, V.V.
(2017). Methods for Studying Interactions Between Atg8/LC3/GABARAP and LIR-Containing Proteins. ,
Klionsky, D.J., Abdelmohsen, K., Abe, A., Abedin, M.J., Abeliovich, H., Acevedo Arozena, A., Adachi, H., Adams, C.M., Adams, P.D., Adeli, K., et al.
(2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy,
(2016). Erratum. Autophagy,
Habisov, S., Huber, J., Ichimura, Y., Akutsu, M., Rogova, N., Loehr, F., McEwan, D.G., Johansen, T., Dikic, I., Doetsch, V., et al.
(2016). Structural and Functional Analysis of a Novel Interaction Motif within UFM1-activating Enzyme 5 (UBA5) Required for Binding to Ubiquitin-like Proteins and Ufmylation. Journal of biological chemistry,
Rossanese, O., Eccles, S., Springer, C., Swain, A., Raynaud, F.I., Workman, P. & Kirkin, V.
(2016). The pharmacological audit trail (PhAT): Use of tumor models to address critical issues in the preclinical development of targeted anticancer drugs. Drug discovery today: disease models,
Habisov, S. & Kirkin, V.
(2015). Caging the Elephant: Selective Autophagy Tackles Giant Intracellular Protein Crystals. Molecular cell,
Rogov, V., Dötsch, V., Johansen, T. & Kirkin, V.
(2014). Interactions between Autophagy Receptors and Ubiquitin-like Proteins Form the Molecular Basis for Selective Autophagy. Molecular cell,
Klionsky, D.J., Abdalla, F.C., Abeliovich, H., Abraham, R.T., Acevedo-Arozena, A., Adeli, K., Agholme, L., Agnello, M., Agostinis, P., Aguirre-Ghiso, J.A., et al.
(2012). Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy,
Alemu, E.A., Lamark, T., Torgersen, K.M., Birgisdottir, A.B., Larsen, K.B., Jain, A., Olsvik, H., Øvervatn, A., Kirkin, V. & Johansen, T., et al.
(2012). ATG8 Family Proteins Act as Scaffolds for Assembly of the ULK Complex. Journal of biological chemistry,
Kirkin, V. & Dikic, I.
(2011). Ubiquitin networks in cancer. Current opinion in genetics & development,
Lückerath, K., Kirkin, V., Melzer, I.M., Thalheimer, F.B., Siele, D., Milani, W., Adler, T., Aguilar-Pimentel, A., Horsch, M., Michel, G., et al.
(2011). Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain. Blood,
Fas ligand (FasL) not only induces apoptosis in Fas receptor-bearing target cells, it is also able to transmit signals into the FasL-expressing cell via its intracellular domain (ICD). Recently, we described a Notch-like proteolytic processing of FasL that leads to the release of the FasL ICD into the cytoplasm and subsequent translocation into the nucleus where it may influence gene transcription. To study the molecular mechanism underlying such reverse FasL signaling in detail and to analyze its physiological importance in vivo, we established a knockout/knockin mouse model, in which wild-type FasL was replaced with a deletion mutant lacking the ICD. Our results demonstrate that FasL ICD signaling impairs activation-induced proliferation in B and T cells by diminishing phosphorylation of phospholipase C γ, protein kinase C, and extracellular signal-regulated kinase 1/2. We also demonstrate that the FasL ICD interacts with the transcription factor lymphoid-enhancer binding factor-1 and inhibits lymphoid-enhancer binding factor-1–dependent transcription. In vivo, plasma cell numbers, generation of germinal center B cells, and, consequently, production of antigen-specific immunoglobulin M antibodies in response to immunization with T cell–dependent or T cell–independent antigen are negatively affected in presence of the FasL ICD, suggesting that FasL reverse signaling participates in negative fine-tuning of certain immune responses..
Dikic, I., Johansen, T. & Kirkin, V.
(2010). Selective Autophagy in Cancer Development and Therapy. Cancer research,
Novak, I., Kirkin, V., McEwan, D.G., Zhang, J., Wild, P., Rozenknop, A., Rogov, V., Löhr, F., Popovic, D., Occhipinti, A., et al.
(2010). Nix is a selective autophagy receptor for mitochondrial clearance. Embo reports,
Shimokawa, N., Haglund, K., Hölter, S.M., Grabbe, C., Kirkin, V., Koibuchi, N., Schultz, C., Rozman, J., Hoeller, D., Qiu, C.-., et al.
(2010). CIN85 regulates dopamine receptor endocytosis and governs behaviour in mice. The embo journal,
Kirkin, V., Lamark, T., Sou, Y.-., Bjørkøy, G., Nunn, J.L., Bruun, J.-., Shvets, E., McEwan, D.G., Clausen, T.H., Wild, P., et al.
(2009). A Role for NBR1 in Autophagosomal Degradation of Ubiquitinated Substrates. Molecular cell,
Kirkin, V., McEwan, D.G., Novak, I. & Dikic, I.
(2009). A Role for Ubiquitin in Selective Autophagy. Molecular cell,
Lamark, T., Kirkin, V., Dikic, I. & Johansen, T.
(2009). NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets. Cell cycle,
Kirkin, V., Lamark, T., Johansen, T. & Dikic, I.
(2009). NBR1 co-operates with p62 in selective autophagy of ubiquitinated targets. Autophagy,
Kirkin, V. & Dikic, I.
(2007). Role of ubiquitin- and Ubl-binding proteins in cell signaling. Current opinion in cell biology,
Kirkin, V., Cahuzac, N., Guardiola-Serrano, F., Huault, S., Lückerath, K., Friedmann, E., Novac, N., Wels, W.S., Martoglio, B., Hueber, A.-., et al.
(2007). The Fas ligand intracellular domain is released by ADAM10 and SPPL2a cleavage in T-cells. Cell death & differentiation,
Cahuzac, N., Baum, W., Kirkin, V., Conchonaud, F., Wawrezinieck, L., Marguet, D., Janssen, O., Zörnig, M. & Hueber, A.-.
(2006). Fas ligand is localized to membrane rafts, where it displays increased cell death–inducing activity. Blood,
Fas ligand (FasL), a member of the TNF protein family, potently induces cell death by activating its matching receptor Fas. Fas-mediated killing plays a critical role in naturally and pathologically occurring cell death, including development and homeostasis of the immune system. In addition to its receptor-interacting and cell death–inducing extracellular domain, FasL has a well-conserved intracellular portion with a proline-rich SH3 domain–binding site probably involved in non-apoptotic functions. We report here that, as with the Fas receptor, a fraction of FasL is constitutively localized in rafts. These dynamic membrane microdomains, enriched in sphingolipids and cholesterol, are important for cell signaling and trafficking processes. We show that FasL is partially localized in rafts and that increased amounts of FasL are found in rafts after efficient FasL/Fas receptor interactions. Raft disorganization after cholesterol oxidase treatment and deletions within the intracellular FasL domain diminish raft partitioning and, most important, lead to decreased FasL killing. We conclude that FasL is recruited into lipid rafts for maximum Fas receptor contact and cell death–inducing potency. These findings raise the possibility that certain pathologic conditions may be treated by altering the cell death–inducing capability of FasL with drugs affecting its raft localization..
Baum, W., Kirkin, V., Fernández, S.B., Pick, R., Lettau, M., Janssen, O. & Zörnig, M.
(2005). Binding of the Intracellular Fas Ligand (FasL) Domain to the Adaptor Protein PSTPIP Results in a Cytoplasmic Localization of FasL. Journal of biological chemistry,
Schempp, C., Kiss, J., Kirkin, V., Averbeck, M., Simon-Haarhaus, B., Kremer, B., Termeer, C., Sleeman, J. & Simon, J.
(2005). Hyperforin acts as an Angiogenesis Inhibitorin vitroandin vivo. Planta medica,
Kirkin, V., Joos, S. & Zörnig, M.
(2004). The role of Bcl-2 family members in tumorigenesis. Biochimica et biophysica acta (bba) - molecular cell research,
Kirkin, V., Thiele, W., Baumann, P., Mazitschek, R., Rohde, K., Fellbrich, G., Weich, H., Waltenberger, J., Giannis, A. & Sleeman, J.P., et al.
(2004). MAZ51, an indolinone that inhibits endothelial cell and tumor cell growthin vitro, suppresses tumor growthin vivo. International journal of cancer,
Krishnan, J., Kirkin, V., Steffen, A., Hegen, M., Weih, D., Tomarev, S., Wilting, J. & Sleeman, J.P.
(2003). Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer research,
Schempp, C.M., Kirkin, V., Simon-Haarhaus, B., Kersten, A., Kiss, J., Termeer, C.C., Gilb, B., Kaufmann, T., Borner, C., Sleeman, J.P., et al.
(2002). Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St John's wort that acts by induction of apoptosis. Oncogene,
Kirkin, V., Mazitschek, R., Krishnan, J., Steffen, A., Waltenberger, J., Pepper, M.S., Giannis, A. & Sleeman, J.P.
(2001). Characterization of indolinones which preferentially inhibit VEGF-C- and VEGF-D-induced activation of VEGFR-3 rather than VEGFR-2. European journal of biochemistry,
Sleeman, J.P., Krishnan, J., Kirkin, V. & Baumann, P.
(2001). Markers for the lymphatic endothelium: In search of the holy grail?. Microscopy research and technique,
Wagner, S., Vlachogiannis, G., De Haven Brandon, A., Valenti, M., Box, G., Jenkins, L., Mancusi, C., Self, A., Manodoro, F., Assiotis, I., et al.
Suppression of interferon gene expression overcomes resistance to MEK inhibition in KRAS-mutant colorectal cancer. Oncogene,
Chung, Y.-., Andrejeva, G., Gowan, S., Lin, G., Wong Te Fong, A.-., Shamsaei, E., Parkes, H.G., Mui, J., Raynaud, F.I., Asad, Y., et al.
De novo phosphatidylcholine synthesis is required for autophagosome membrane formation and maintenance during autophagy. Autophagy,