bims-apauto 2023-02-19 papers

Issue of 2023–02–19
five papers selected by
Su Hyun Lee, Harvard University

Nat Commun. 2023 Feb 16. 14(1): 870

Spatial proteomics reveals secretory pathway disturbances caused by neuropathy-associated TECPR2.

Karsten Nalbach, Martina Schifferer, Debjani Bhattacharya, Hung Ho-Xuan, Wei Tseng, Luis A Williams, Alexandra Stolz, Stefan F Lichtenthaler, Zvulun Elazar, Christian Behrends.

Hereditary sensory and autonomic neuropathy 9 (HSAN9) is a rare fatal neurological disease caused by mis- and nonsense mutations in the gene encoding for Tectonin β-propeller repeat containing protein 2 (TECPR2). While TECPR2 is required for lysosomal consumption of autophagosomes and ER-to-Golgi transport, it remains elusive how exactly TECPR2 is involved in autophagy and secretion and what downstream sequels arise from defective TECPR2 due to its involvement in these processes. To address these questions, we determine molecular consequences of TECPR2 deficiency along the secretory pathway. By employing spatial proteomics, we describe pronounced changes with numerous proteins important for neuronal function being affected in their intracellular transport. Moreover, we provide evidence that TECPR2's interaction with the early secretory pathway is not restricted to COPII carriers. Collectively, our systematic profiling of a HSAN9 cell model points to specific trafficking and sorting defects which might precede autophagy dysfunction upon TECPR2 deficiency.

DOI: https://doi.org/10.1038/s41467-023-36553-6

Cell Cycle. 2023 Feb 14. 1-3

SQSTM1 facilitates oocyte maturation through inducing ACLY degradation mediated by selective autophagy.

Heide Schatten.

Selective autophagy specifically eliminates certain intracellular substrates through the autophagy pathway. Organelles and aggregation-prone proteins can be degraded through the autophagy receptor protein SQSTM1/p62, which renders them a promising therapeutic approach against infertility. He et al. demonstrate that blocking of autophagy in cumulus granulosa cells can directly attenuate citrate levels and in turn affect oocyte maturation quality. Further findings show that SQSTM1 connects K63-polyubiquitinated ACLY (ATP citrate lyase) during the process of selective autophagic degradation, which further compromises the homeostasis of citrate. Therefore, the quality of oocyte meiotic maturation can be evaluated by the levels of selective autophagy in cumulus granulosa cells.

Keywords: ACLY; Sqstm1/P62; citrate; meiotic resumption; selective autophagy

DOI: https://doi.org/10.1080/15384101.2023.2176673

Autophagy. 2023 Feb 13.

Autophagy in synapse formation and brain wiring.

Bassem A Hassan, P Robin Hiesinger.

A recent characterization of the role of autophagy in two different neuron types during brain development in Drosophila revealed two different mechanisms to regulate synapse formation. In photoreceptor neurons, autophagosome formation in synaptogenic filopodia destabilizes presumptive synaptic contacts and thereby restricts incorrect synaptic partnerships. In dorsal cluster neurons, autophagy is actively suppressed to keep mature synapses stable during axonal branching. These findings indicate that different neuron types can require activation or suppression of synaptic autophagy during the same developmental period to ensure proper synapse formation and brain connectivity.

Keywords: active zone; brain development; filopodia; neuron; neuronal autophagy; synapse; synaptic autophagy; synaptogenesis

DOI: https://doi.org/10.1080/15548627.2023.2179778

Sci Adv. 2023 Feb 15. 9(7): eadg2997

Structural basis for ATG9A recruitment to the ULK1 complex in mitophagy initiation.

Xuefeng Ren, Thanh N Nguyen, Wai Kit Lam, Cosmo Z Buffalo, Michael Lazarou, Adam L Yokom, James H Hurley.

The assembly of the autophagy initiation machinery nucleates autophagosome biogenesis, including in the PINK1- and Parkin-dependent mitophagy pathway implicated in Parkinson's disease. The structural interaction between the sole transmembrane autophagy protein, autophagy-related protein 9A (ATG9A), and components of the Unc-51-like autophagy activating kinase (ULK1) complex is one of the major missing links needed to complete a structural map of autophagy initiation. We determined the 2.4-Å x-ray crystallographic structure of the ternary structure of ATG9A carboxyl-terminal tail bound to the ATG13:ATG101 Hop1/Rev7/Mad2 (HORMA) dimer, which is part of the ULK1 complex. We term the interacting portion of the extreme carboxyl-terminal part of the ATG9A tail the "HORMA dimer-interacting region" (HDIR). This structure shows that the HDIR binds to the HORMA domain of ATG101 by β sheet complementation such that the ATG9A tail resides in a deep cleft at the ATG13:ATG101 interface. Disruption of this complex in cells impairs damage-induced PINK1/Parkin mitophagy mediated by the cargo receptor NDP52.

DOI: https://doi.org/10.1126/sciadv.adg2997

Autophagy. 2023 Feb 13.

CLU (clusterin) promotes mitophagic degradation of MSX2 through an AKT-DNM1L/Drp1 axis to maintain SOX2-mediated stemness in oral cancer stem cells.

Prakash P Praharaj, Srimanta Patra, Soumya R Mishra, Subhadip Mukhopadhyay, Daniel J Klionsky, Shankargouda Patil, Sujit K Bhutia.

Mitophagy regulates cancer stem cell (CSC) populations affecting tumorigenicity and malignancy in various cancer types. Here, we report that cisplatin treatment led to the activation of higher mitophagy through regulating CLU (clusterin) levels in oral CSCs. Moreover, both the gain-of-function and loss-of-function of CLU indicated its mitophagy-specific role in clearing damaged mitochondria. CLU also regulates mitochondrial fission by activating the Ser/Thr kinase AKT, which triggered phosphorylation of DNM1L/DRP1 at the serine 616 residue initiating mitochondrial fission. More importantly, we also demonstrated that CLU-mediated mitophagy positively regulates oral CSCs through mitophagic degradation of MSX2 (msh homeobox 2), preventing its nuclear translocation from suppressing SOX2 activity and subsequent inhibition of cancer stemness and self-renewal ability. However, CLU knockdown disturbed mitochondrial metabolism generating excessive mitochondrial superoxide, which improves the sensitivity to cisplatin in oral CSCs. Notably, our results showed that CLU-mediated cytoprotection relies on SOX2 expression. SOX2 inhibition through genetic (shSOX2) and pharmacological (KRX-0401) strategies reverses CLU-mediated cytoprotection, sensitizing oral CSCs towards cisplatin-mediated cell death.

Keywords: Cancer stem cells; MSX2; SOX2; clusterin; mitophagy

DOI: https://doi.org/10.1080/15548627.2023.2178876