bims-raghud 2024-09-29 papers

Issue of 2024–09–29
three papers selected by
Irene Sambri, TIGEM

Nat Commun. 2024 Sep 27. 15(1): 8334

USF2 and TFEB compete in regulating lysosomal and autophagy genes.

Jaebeom Kim, Young Suk Yu, Yehwa Choi, Do Hui Lee, Soobin Han, Junhee Kwon, Taichi Noda, Masahito Ikawa, Dongha Kim, Hyunkyung Kim, Andrea Ballabio, Keun Il Kim, Sung Hee Baek.

Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases.

DOI: https://doi.org/10.1038/s41467-024-52600-2

FEBS J. 2024 Sep 26.

Senescence in the ageing skin: a new focus on mTORC1 and the lysosome.

Phineas Smith, Bernadette Carroll.

Ageing is defined as the progressive loss of tissue function and regenerative capacity and is caused by both intrinsic factors i.e. the natural accumulation of damage, and extrinsic factors i.e. damage from environmental stressors. Cellular senescence, in brief, is an irreversible exit from the cell cycle that occurs primarily in response to excessive cellular damage, such as from ultraviolet (UV) exposure and oxidative stress, and it has been comprehensively demonstrated to contribute to tissue and organismal ageing. In this review, we will focus on the skin, an organ which acts as an essential protective barrier against injury, insults, and infection. We will explore the evidence for the existence and contribution of cellular senescence to skin ageing. We discuss the known molecular mechanisms driving senescence in the skin, with a focus on the dysregulation of the master growth regulator, mechanistic Target of Rapamycin Complex 1 (mTORC1). We explore the interplay of dysregulated mTORC1 with lysosomes and how they contribute to senescence phenotypes.

Keywords: ageing; lysosome; mTORC1; senescence; skin

DOI: https://doi.org/10.1111/febs.17281

Autophagy. 2024 Sep 26.

SMURF1 mediates damaged lysosomal homeostasis by ubiquitinating PPP3CB to promote the activation of TFEB.

Qin Xia, Xuan Liu, Lu Zhong, Jun Qu, Lei Dong.

The calcium-activated phosphatase PPP3/calcineurin dephosphorylates TFEB (transcription factor EB) to trigger its nuclear translocation and the activation of macroautophagic/autophagic targets. However, the detailed molecular mechanism regulating TFEB activation remains poorly understood. Here, we highlighted the importance of SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) in the activation of TFEB for lysosomal homeostasis. SMURF1 deficiency prevents the calcium-triggered ubiquitination of the catalytic subunit of PPP3/calcineurin in a manner consistent with defective autophagic degradation of damaged lysosomes. Mechanically, PPP3CB/CNA2 plays a bridging role in the recruitment of SMURF1 by LGALS3 (galectin 3) upon lysosome damage. Importantly, PPP3CB increases the dissociation of the N-terminal tail (NT) and C-terminal carbohydrate-recognition domain (CRD) of LGALS3, which may promote the formation of open conformers in a PPP3CB dephosphorylation activity-dependent manner. In addition, PPP3CB is ubiquitinated at lysine 146 by the recruited SMURF1 in response to intracellular calcium stimulation. The K63-linked ubiquitination of PPP3CB enhances the recruitment of TFEB. Moreover, TFEB directly interacts with both PPP3CB and the regulatory subunit PPP3R1 which facilitate the conformational correction of TFEB for its activation for the transcription of TFEB-targeted genes. Altogether, our results highlighted a critical mechanism for the regulation of PPP3/calcineurin activity via its ubiquitin ligase SMURF1 in response to lysosomal membrane damage, which may account for a potential target for the treatment of stress-related diseases.

Keywords: Autophagy; PPP3/calcineurin; SMURF1; TFEB; lysosomal homeostasis

DOI: https://doi.org/10.1080/15548627.2024.2407709