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AUTOPHAGY

Autophagy without conjugation

Nature Structural & Molecular Biology volume 26, pages 249–250 (2019)Cite this article

Ubiquitin and ubiquitin-like proteins (UBLs) are essential regulators of a multitude of cellular processes, including autophagy. It is known that these proteins relay their effects by covalently modifying their substrate molecules. As an exception to this norm, Pang et al. report a novel phenomenon in which the UBL ATG12 interacts with its substrate ATG5 in a non-covalent fashion to promote autophagy in apicomplexan parasites and some yeasts.

Ubiquitin and UBLs such as ATG8, ATG12, NEDD8, etc. are small proteins that have been linked to the regulation of diverse cellular functions, including intracellular degradation pathways, via the proteasome and autophagy networks1. UBLs share structural similarity with ubiquitin. They are activated, conjugated and released from their substrates by enzymatic processes that are similar to those of the ubiquitin enzymatic cascade. Specific E1 (activating), E2 (conjugating) and E3 (ligating) enzymes aid in the conjugation of UBLs to their intracellular substrates. One of the processes controlled in this way is autophagosome formation, which requires ATG12 and ATG82,3. The C-terminal glycine of ATG12 is covalently attached to the side chain of ATG5 through reactions catalyzed by E1 enzyme ATG7 and E2 enzyme ATG10; this thereby forms a stable ATG12–ATG5 conjugate that then assists in covalently linking ATG8 to the amino group of phosphatidylethanolamine4 (Fig. 1). Now Pang et al. have for the first time observed an atypical non-covalent interaction between ATG12 and ATG5 in the apicomplexan parasites Plasmodium and Toxoplasma and Pichiaceae yeasts. They report that the non-covalent interaction between ATG12 and ATG5 is fully functional and is presumably of evolutionary advantage in unicellular organisms5 (Fig. 1).

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Fig. 1: Covalent and non-covalent interactions between ATG12 and ATG5.

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Authors and Affiliations

  1. Department of Infectious Diseases, Genentech, South San Francisco, CA, USA

    Varnesh Tiku & Ivan Dikic

  2. Institute of Biochemistry II, Goethe University Frankfurt–Medical Faculty, University Hospital, Frankfurt am Main, Germany

    Ivan Dikic

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  1. Varnesh Tiku
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  2. Ivan Dikic
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Correspondence to Ivan Dikic.

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The authors declare no competing interests.

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Tiku, V., Dikic, I. Autophagy without conjugation. Nat Struct Mol Biol 26, 249–250 (2019). https://doi.org/10.1038/s41594-019-0207-0

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