Alf Håkon Lohsen Lystad

• Kaur, Namrita; Carlsson, Sven R & Lystad, Alf Håkon Lohsen (2023). The separate axes of TECPR1 and ATG16L1 in CASM. Autophagy. ISSN 1554-8627. p. 1–2. doi: 10.1080/15548627.2023.2255462. Full text in Research Archive
• Kaur, Namrita; de la Ballina, Laura R; Haukaas, Håvard Styrkestad; Torgersen, Maria Lyngaas; Radulovic, Maja & Munson, Michael J [Show all 11 contributors for this article] (2023). TECPR1 is activated by damage-induced sphingomyelin exposure to mediate noncanonical autophagy. EMBO Journal. ISSN 0261-4189. 42(17), p. 1–19. doi: 10.15252/embj.2022113105. Full text in Research Archive
• Radulovic, Maja; Wenzel, Eva; Gilani, Sania; Holland, Lya KK; Lystad, Alf Håkon Lohsen & Phuyal, Santosh [Show all 12 contributors for this article] (2022). Cholesterol transfer via endoplasmic reticulum contacts mediates lysosome damage repair. EMBO Journal. ISSN 0261-4189. 41:e112677, p. 1–18. doi: 10.15252/embj.2022112677. Full text in Research Archive Show summary

  Lysosome integrity is essential for cell viability, and lesions in lysosome membranes are repaired by the ESCRT machinery. Here, we describe an additional mechanism for lysosome repair that is activated independently of ESCRT recruitment. Lipidomic analyses showed increases in lysosomal phosphatidylserine and cholesterol after damage. Electron microscopy demonstrated that lysosomal membrane damage is rapidly followed by the formation of contacts with the endoplasmic reticulum (ER), which depends on the ER proteins VAPA/B. The cholesterol-binding protein ORP1L was recruited to damaged lysosomes, accompanied by cholesterol accumulation by a mechanism that required VAP–ORP1L interactions. The PtdIns 4-kinase PI4K2A rapidly produced PtdIns4P on lysosomes upon damage, and knockout of PI4K2A inhibited damage-induced accumulation of ORP1L and cholesterol and led to the failure of lysosomal membrane repair. The cholesterol–PtdIns4P transporter OSBP was also recruited upon damage, and its depletion caused lysosomal accumulation of PtdIns4P and resulted in cell death. We conclude that ER contacts are activated on damaged lysosomes in parallel to ESCRTs to provide lipids for membrane repair, and that PtdIns4P generation and removal are central in this response.

• Xu, Jing; Yang, Kevin C; Go, Nancy Erro; Colborne, Shane; Ho, Cally J & Hosseini-Beheshti, Elham [Show all 11 contributors for this article] (2022). Chloroquine treatment induces secretion of autophagy-related proteins and inclusion of Atg8-family proteins in distinct extracellular vesicle populations. Autophagy. ISSN 1554-8627. 18(11), p. 2547–2560. doi: 10.1080/15548627.2022.2039535. Full text in Research Archive
• Søreng, Kristiane; Pankiv, Serhiy; Bergsmark, Camilla; Haugsten, Ellen Margrethe; Dahl, Anette Kathinka & de la Ballina, Laura R [Show all 9 contributors for this article] (2022). ALFY localizes to early endosomes and cellular protrusions to facilitate directional cell migration . Journal of Cell Science. ISSN 0021-9533. 135(4). doi: 10.1242/jcs.259138. Full text in Research Archive
• Corkery, Dale P.; Nadeem, Aftab; Aung, Kyaw Min; Hassan, Ahmed; Liu, Tao & Cervantes-Rivera, Ramón [Show all 14 contributors for this article] (2021). Vibrio cholerae cytotoxin MakA induces noncanonical autophagy resulting in the spatial inhibition of canonical autophagy. Journal of Cell Science. ISSN 0021-9533. 134(5). doi: 10.1242/jcs.252015.
• Kumar, Suresh; Javed, Ruheena; Mudd, Michal H.; Pallikkuth, Sandeep; Lidke, Keith A. & Jain, Ashish [Show all 22 contributors for this article] (2021). Mammalian hybrid pre-autophagosomal structure HyPAS generates autophagosomes. Cell. ISSN 0092-8674. 184(24), p. 5950–5969. doi: 10.1016/j.cell.2021.10.017. Show summary

  The biogenesis of mammalian autophagosomes remains to be fully defined. Here, we used cellular and in vitro membrane fusion analyses to show that autophagosomes are formed from a hitherto unappreciated hybrid membrane compartment. The autophagic precursors emerge through fusion of FIP200 vesicles, derived from the cis-Golgi, with endosomally derived ATG16L1 membranes to generate a hybrid pre-autophagosomal structure, HyPAS. A previously unrecognized apparatus defined here controls HyPAS biogenesis and mammalian autophagosomal precursor membranes. HyPAS can be modulated by pharmacological agents whereas its formation is inhibited upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or by expression of SARS-CoV-2 nsp6. These findings reveal the origin of mammalian autophagosomal membranes, which emerge via convergence of secretory and endosomal pathways, and show that this process is targeted by microbial factors such as coronaviral membrane-modulating proteins

• Durgan, Joanne; Lystad, Alf Håkon Lohsen; Sloan, Katherine; Carlsson, Sven R.; Wilson, Michael I. & Marcassa, Elena [Show all 14 contributors for this article] (2021). Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine. Molecular Cell. ISSN 1097-2765. 81(9), p. 2031–2040.e8. doi: 10.1016/j.molcel.2021.03.020. Full text in Research Archive
• Giovannucci, Tatiana A.; Salomons, Florian A.; Stoy, Henriette; Herzog, Laura K.; Xu, Shanshan & Qian, Weixing [Show all 15 contributors for this article] (2021). Identification of a novel compound that simultaneously impairs the ubiquitin-proteasome system and autophagy. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2021.1988359. Full text in Research Archive
• Klionsky, Daniel J.; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud Khaled; Abdoli, Asghar & Abudu, Yakubu Princely [Show all 50 contributors for this article] (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) . Autophagy. ISSN 1554-8627. 17(1), p. 1–382. doi: 10.1080/15548627.2020.1797280.
• Munson, Michael Joseph; Mathai, Benan J.; Ng, Matthew; Trachsel Moncho, Laura Cristina; de la Ballina, Laura R & Schultz, Sebastian W. [Show all 13 contributors for this article] (2021). GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature Communications. ISSN 2041-1723. 12(1). doi: 10.1038/s41467-021-26331-7. Full text in Research Archive Show summary

  The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as regulators of PRKN-independent mitophagy, with both being dispensable for PRKN- dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD facilitates recruitment of ULK1/ATG13 to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C. elegans or knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation.

• Hamaoui, Daniel; Cossé, Mathilde M.; Mohan, Jagan; Lystad, Alf Håkon; Wollert, Thomas & Subtil, Agathe (2020). The Chlamydia effector CT622/TaiP targets a nonautophagy related function of ATG16L1. Proceedings of the National Academy of Sciences of the United States of America. ISSN 0027-8424. 117(43), p. 26784–26794. doi: 10.1073/pnas.2005389117. Full text in Research Archive
• Melia, Thomas; Lystad, Alf Håkon & Simonsen, Anne (2020). Autophagosome biogenesis: From membrane growth to closure. Journal of Cell Biology. ISSN 0021-9525. 219(6). doi: 10.1083/jcb.202002085. Full text in Research Archive
• Lystad, Alf Håkon & Simonsen, Anne (2019). Mechanisms and Pathophysiological Roles of the ATG8 Conjugation Machinery. Cells. ISSN 2073-4409. 8(9). doi: 10.3390/cells8090973. Full text in Research Archive Show summary

  Since their initial discovery around two decades ago, the yeast autophagy-related (Atg)8 protein and its mammalian homologues of the light chain 3 (LC3) and γ-aminobutyric acid receptor associated proteins (GABARAP) families have been key for the tremendous expansion of our knowledge about autophagy, a process in which cytoplasmic material become targeted for lysosomal degradation. These proteins are ubiquitin-like proteins that become directly conjugated to a lipid in the autophagy membrane upon induction of autophagy, thus providing a marker of the pathway, allowing studies of autophagosome biogenesis and maturation. Moreover, the ATG8 proteins function to recruit components of the core autophagy machinery as well as cargo for selective degradation. Importantly, comprehensive structural and biochemical in vitro studies of the machinery required for ATG8 protein lipidation, as well as their genetic manipulation in various model organisms, have provided novel insight into the molecular mechanisms and pathophysiological roles of the mATG8 proteins. Recently, it has become evident that the ATG8 proteins and their conjugation machinery are also involved in intracellular pathways and processes not related to autophagy. This review focuses on the molecular functions of ATG8 proteins and their conjugation machinery in autophagy and other pathways, as well as their links to disease.

• Herzog, Laura K; Kevei, Eva; Marchante, Ricardo; Botther, Claudia; Bindesbøll, Christian & Lystad, Alf Håkon [Show all 12 contributors for this article] (2019). The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy. Aging Cell. ISSN 1474-9718. doi: 10.1111/acel.13051. Full text in Research Archive Show summary

  The pathology of spinocerebellar ataxia type 3, also known as Machado‐Joseph disease, is triggered by aggregation of toxic ataxin‐3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX‐3, the nematode orthologue of ATXN3, together with the ubiquitin‐directed segregase CDC‐48, regulates longevity in Caenorhabditis elegans. Here, we demonstrate that the long‐lived cdc‐48.1; atx‐3 double mutant displays reduced viability under prolonged starvation conditions that can be attributed to the loss of catalytically active ATX‐3. Reducing the levels of the autophagy protein BEC‐1 sensitized worms to the effect of ATX‐3 deficiency, suggesting a role of ATX‐3 in autophagy. In support of this conclusion, the depletion of ATXN3 in human cells caused a reduction in autophagosomal degradation of proteins. Surprisingly, reduced degradation in ATXN3‐depleted cells coincided with an increase in the number of autophagosomes while levels of lipidated LC3 remained unaffected. We identified two conserved LIR domains in the catalytic Josephin domain of ATXN3 that directly interacted with the autophagy adaptors LC3C and GABARAP in vitro. While ATXN3 localized to early autophagosomes, it was not subject to lysosomal degradation, suggesting a transient regulatory interaction early in the autophagic pathway. We propose that the deubiquitylase ATX‐3/ATXN3 stimulates autophagic degradation by preventing superfluous initiation of autophagosomes, thereby promoting an efficient autophagic flux important to survive starvation.

• Herhaus, Lina; Bhaskara, Ramachandra M; Lystad, Alf Håkon; Gestal-Mato, Uxia; Covarrubias-Pinto, Adriana & Bonn, Florian [Show all 9 contributors for this article] (2019). TBK1-mediated phosphorylation of LC3C and GABARAP-L2 controls autophagosome shedding by ATG4 protease. EMBO Reports. ISSN 1469-221X. doi: 10.15252/embr.201948317. Full text in Research Archive
• Lystad, Alf Håkon; Carlsson, Sven R; Rodriguez de la Ballina, Laura; Kauffman, Karlina J; Nag, Shanta & Yoshimori, Tamotsu [Show all 8 contributors for this article] (2019). Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation in autophagy-related processes. Nature Cell Biology. ISSN 1465-7392. 21(3), p. 372–383. doi: 10.1038/s41556-019-0274-9. Full text in Research Archive
• Abudu, Yakubu Princely; Pankiv, Serhiy; Mathai, Benan John; Lystad, Alf Håkon; Bindesbøll, Christian & Brenne, Hanne Britt [Show all 14 contributors for this article] (2019). NIPSNAP1 and NIPSNAP2 act as “eat-me signal” for mitophagy. Developmental Cell. ISSN 1534-5807. 49(4), p. 509–525.e12. doi: 10.1016/j.devcel.2019.03.013. Full text in Research Archive
• Kauffman, Karlina J; Yu, Shenliang; Jin, Jiaxin; Mugo, Brian; Nguyen, Nathan & O'Brien, Aidan [Show all 9 contributors for this article] (2018). Delipidation of mammalian Atg8-family proteins by each of the four ATG4 proteases. Autophagy. ISSN 1554-8627. 14(6), p. 992–1010. doi: 10.1080/15548627.2018.1437341.
• Holland, Petter; Knævelsrud, Helene; Søreng, Kristiane; Mathai, Benan John; Lystad, Alf Håkon & Pankiv, Serhiy [Show all 16 contributors for this article] (2016). HS1BP3 negatively regulates autophagy by modulation of phosphatidic acid levels. Nature Communications. ISSN 2041-1723. 7. doi: 10.1038/ncomms13889. Full text in Research Archive
• Dragich, Joanna M; Kuwajima, Takaaki; Hirose-Ikeda, Megumi; Yoon, Michael S; Eenjes, Evelien & Bosco, Joan R [Show all 18 contributors for this article] (2016). Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain. eLIFE. ISSN 2050-084X. 5(September). doi: 10.7554/eLife.14810.
• Lystad, Alf Håkon & Simonsen, Anne (2016). Phosphoinositide-binding proteins in autophagy. FEBS Letters. ISSN 0014-5793. p. 2454–2468. doi: 10.1002/1873-3468.12286.
• Lystad, Alf Håkon & Simonsen, Anne (2015). Assays to monitor aggrephagy. Methods. ISSN 1046-2023. 75, p. 112–119. doi: 10.1016/j.ymeth.2014.12.019.
• Lystad, Alf Håkon; Ichimura, Yoshinobu; Takagi, K; Yang, Yinjie; Pankiv, Serhiy & Kanegae, Yumi [Show all 12 contributors for this article] (2014). Structural determinants in GABARAP required for the selective binding and recruitment of ALFY to LC3B-positive structures. EMBO Reports. ISSN 1469-221X. 15(5), p. 557–565. doi: 10.1002/embr.201338003.
• Isakson, Pauline; Lystad, Alf Håkon; Breen, Kamilla; Koster, Gerbrand; Stenmark, Harald Alfred & Simonsen, Anne (2013). TRAF6 mediates ubiquitination of KIF23/MKLP1 and is required for midbody ring degradation by selective autophagy. Autophagy. ISSN 1554-8627. 9(12), p. 1955–1964. doi: 10.4161/auto.26085.

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• Lystad, Alf Håkon; Carlsson, Sven R. & Simonsen, Anne (2019). Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes. Autophagy. ISSN 1554-8627. 15(8), p. 1485–1486. doi: 10.1080/15548627.2019.1618100. Full text in Research Archive Show summary

  The machinery that decorates autophagic membranes with lipid-conjugated LC3/GABARAP is not yet fully understood. We recently reported the purification of the full-length ATG12–ATG5-ATG16L1 complex, and in reconstitution experiments with purified ATG7, ATG3, and LC3/GABARAP in vitro, together with rescue experiments in knockout cells, important aspects of the complete lipidation reaction were revealed. Hitherto unobserved membrane-binding regions in ATG16L1 were found, contributing to properties that explain the crucial role of this protein in membrane targeting and LC3/GABARAP lipidation in macroautophagy/autophagy and other related processes.

• Lystad, Alf Håkon; Sporstol, Marita; Foroughi, Masoud; Roos, Norbert; Berg, Trond & Eskild, Winnie (2009). Regulation of VEGF expression by vitamin D i hepatic stellate cells - possible attenuation by the nuclear receptor coregulator NCY-G1.
• Lystad, Alf Håkon; Sporstol, Marita; Foroughi, Masoud; Roos, Norbert; Berg, Trond & Eskild, Winnie (2009). Regulation of VEGF expression by vitamin D in hepatic stellate cells - possible attenuation by the nuclear receptor coregulator NCU-G1.

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