Abstract Acetylation is an increasing area of focus for cancer research as it is closely related to a variety of cellular processes through modulation of histone and non-histone proteins. However, broadly targeting acetylation threatens to yield nonselective toxic effects owing to the vital role of acetylation in cellular function. There is thus a pressing need to elucidate and characterize the specific cancer-relevant roles of acetylation for future therapeutic design. Acetylation-mediated protein homeostasis is an example of selective acetylation that affects a myriad of proteins as well as their correlated functions. We review recent examples of acetylation-mediated protein homeostasis that have emerged as key contributors to tumorigenesis, tumor proliferation, metastasis, and/or drug resistance, and we discuss their implications for future exploration of this intriguing phenomenon.
Aikio M, Odeh HM, Wobst HJ, Lee BL, Chan Ú, Mauna JC, Mack KL, Class B, Ollerhead TA, Ford AF, Barbieri EM, Cupo RR, Drake LE, Smalley JL, Lin YT, Lam S, Thomas R, Castello N, Baral A, Beyer JN, Najar MA, Dunlop J, Gitler AD, Javaherian A, Kaye JA, Burslem GM, Brown DG, Donnelly CJ, Finkbeiner S, Moss SJ, Brandon NJ, Shorter J. Opposing roles of p38α-mediated phosphorylation and PRMT1-mediated arginine methylation in driving TDP-43 proteinopathy. Cell Rep. 2025 Jan 28;44(1):115205. doi: 10.1016/j.celrep.2024.115205. Epub 2025 Jan 14. Erratum in: Cell Rep. 2025 Mar 25;44(3):115386. doi: 10.1016/j.celrep.2025.115386. PMID: 39817908; PMCID: PMC11831926.
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder typically characterized by insoluble inclusions of hyperphosphorylated TDP-43. The mechanisms underlying toxic TDP-43 accumulation are not understood. Persistent activation of p38 mitogen-activated protein kinase (MAPK) is implicated in ALS. However, it is unclear how p38 MAPK affects TDP-43 proteinopathy. Here, we show that p38α MAPK inhibition reduces pathological TDP-43 phosphorylation, aggregation, cytoplasmic mislocalization, and neurotoxicity. Remarkably, p38α MAPK inhibition mitigates aberrant TDP-43 phenotypes in diverse ALS patient-derived motor neurons. p38α MAPK phosphorylates TDP-43 at pathological S409/S410 and S292, which reduces TDP-43 liquid-liquid phase separation (LLPS) but allows pathological TDP-43 aggregation. Moreover, we establish that PRMT1 methylates TDP-43 at R293. Importantly, S292 phosphorylation reduces R293 methylation, and R293 methylation reduces S409/S410 phosphorylation. Notably, R293 methylation permits TDP-43 LLPS and reduces pathological TDP-43 aggregation. Thus, strategies to reduce p38α-mediated TDP-43 phosphorylation and promote PRMT1-mediated R293 methylation could have therapeutic utility for ALS and related TDP-43 proteinopathies.