N6-methyladenosine helps Apostichopus japonicus resist Vibrio splendidus infection by targeting coelomocyte autophagy via the AjULK-AjYTHDF/AjEEF-1α axis

Abstract

N6-Methyladenosine (m6A) modification is one of the most abundant post-transcriptional modifications that can mediate autophagy in various pathological processes. However, the functional role of m6A in autophagy regulation is not well-documented during Vibrio splendidus infection of Apostichopus japonicus. In this study, the inhibition of m6A level by knockdown of methyltransferase-like 3 (AjMETTL3) significantly decreased V. splendidus-induced coelomocyte autophagy and led to an increase in the intracellular V. splendidus burden. In this condition, Unc-51-like kinase 1 (AjULK) displayed the highest differential expression of m6A level. Moreover, knockdown of AjULK can reverse the V. splendidus-mediated autophagy in the condition of AjMETTL3 overexpression. Furthermore, knockdown of AjMETTL3 did not change the AjULK mRNA transcript levels but instead decreased protein levels. Additionally, YTH domain-containing family protein (AjYTHDF) was identified as a reader protein of AjULK and promoted AjULK expression in an m6A-dependent manner. Furthermore, the AjYTHDF-mediated AjULK expression depended on its interaction with translation elongation factor 1-alpha (AjEEF-1α). Altogether, our findings suggest that m6A is involved in resisting V. splendidus infection via facilitating coelomocyte autophagy in AjULK-AjYTHDF/AjEEF-1α-dependent manner, which provides a theoretical basis for disease prevention and therapy in A. japonicus.

In Search of a Function for the N6-Methyladenosine in Epitranscriptome, Autophagy and Neurodegenerative Diseases

“…For example, it is noteworthy that the alteration of unc-51-like autophagy-activating kinase 1 (ULK1) mRNA expression could be post-transcriptionally altered by the m6A RNA modification, triggering a considerable inhibition of autophagy [ 71 ]. Subsequently, many investigations have revealed the effects of m6A modification in the autophagy-related mechanisms [ 20 , 72 ]. The m6A modification could convey inhibitory effects on autophagy, in which the METTL3 might be the key factor involved in the aberrant modification of m6A [ 21 , 73 ].…”

Epitranscriptome Changes in Neurodegenerative Diseases and the Potential Strategy for the Therapeutics

“…For example, it is noteworthy that the alteration of unc-51-like autophagyactivating kinase 1 (ULK1) mRNA expression could be post-transcriptionally altered by the m6A RNA modification, triggering a considerable inhibition of autophagy [71]. Subsequently, many investigations have revealed the effects of m6A modification in the autophagy-related mechanisms [20,72]. The m6A modification could convey inhibitory effects on autophagy, in which the METTL3 might be the key factor involved in the aberrant modification of m6A [21,73].…”