Sir2B

Sir2B (PF3D7_1451400) is an NAD+-dependent histone deacetylase that silences specific subsets of var virulence genes in Plasmodium falciparum, contributing to the mutually exclusive expression that underlies antigenic variation (PMID:19402747). Sir2B silences var subsets defined by their conserved promoter type, and its disruption breaks down mutual exclusion and derepresses these subsets by disrupting the cis spreading of silenced chromatin outward from the var promoter (PMID:19402747). Functionally, Sir2B is distinguished from its family counterpart Sir2A on two counts: it is dispensable for telomere-length regulation, since Sir2B knockouts lack the elongated telomeric repeats seen in Sir2A knockouts (PMID:19402747), and rather than antagonizing H2A.Z it promotes or maintains PfH2A.Z occupancy at active var promoter transcription start sites, which is lost upon Sir2B disruption (PMID:21379342). Sir2B expression is itself repressed at the transcriptional level: PfHsp90 occupies Sir2B promoter-proximal regions and recruits H3K9me3 to impose a heterochromatic state in response to febrile temperature, and reduced Sir2B occupancy at sub-telomeric var promoters correlates with var derepression (PMID:33538363). Its contribution to var regulation is strain-background dependent, with disruption in NF54 and FCR-3 producing no dramatic var expression changes unlike in 3D7 (PMID:25780929).

1. 2009 High

   Establishing whether a second sirtuin beyond Sir2A participates in var silencing, this work showed Sir2B is an NAD+-dependent deacetylase required for silencing specific promoter-defined var subsets and for cis heterochromatin spreading from var promoters.

   Evidence Knockout of Sir2B in P. falciparum with var expression and chromatin assays

   PMID:19402747

   Open questions at the time

   • Direct enzymatic activity and substrate acetyl-lysine targets not defined in this entry
   • Molecular basis of promoter-type selectivity unresolved
   • Mechanism of chromatin spreading not defined at protein-recruitment level
2. 2009 Medium

   To test whether Sir2B shares Sir2A's telomeric role, telomere-length analysis of the knockout showed no repeat elongation, functionally separating Sir2B from telomere end protection.

   Evidence Telomere-length analysis of Sir2B knockout P. falciparum

   PMID:19402747

   Open questions at the time

   • Negative finding does not exclude subtle or context-dependent telomeric contributions
   • Single lab, single comparative readout
3. 2011 Medium

   Addressing how Sir2B acts on active promoters, ChIP showed Sir2B is needed to maintain PfH2A.Z at active var transcription start sites, defining a mechanism opposite to Sir2A's antagonism of H2A.Z.

   Evidence ChIP of PfH2A.Z in Sir2B knockout versus wild-type across lifecycle stages

   PMID:21379342

   Open questions at the time

   • Whether Sir2B acts directly on H2A.Z deposition or indirectly is unresolved
   • Single lab study
4. 2015 Medium

   Testing reproducibility of Sir2B's var role across genetic backgrounds, knockouts in NF54 and FCR-3 produced no dramatic var changes, establishing that Sir2B's regulatory contribution is strain-background dependent.

   Evidence Sir2B disruption in 3D7, NF54, and FCR-3 with qPCR var expression readout

   PMID:25780929

   Open questions at the time

   • Genetic determinants underlying strain-dependence not identified
   • qPCR readout may miss single-locus or chromatin-level effects
5. 2021 Medium

   Addressing how environmental stress feeds into var control, this work showed PfHsp90 represses Sir2B transcription by occupying its promoter and recruiting H3K9me3 under febrile temperature, linking heat stress to Sir2B downregulation and var derepression.

   Evidence ChIP of PfHsp90 and H3K9me3 at Sir2B promoter, qPCR after heat and Hsp90-inhibitor treatment, ChIP of PfSir2 at var promoters

   PMID:33538363

   Open questions at the time

   • How reduced Sir2B protein quantitatively translates to specific var switching is not resolved
   • Direct versus indirect Hsp90-Sir2B promoter contact not distinguished
6. 2022 Low

   Probing stage-specificity of Sir2B stress responsiveness, heat shock raised Sir2B transcript in trophozoites but not rings, and lactate had no effect, refining when Sir2B expression responds to thermal stress.

   Evidence qPCR of Sir2B transcripts after heat shock or lactate in synchronised cultures

   PMID:35031386

   Open questions at the time

   • Single method (qPCR) with no follow-up on protein-level or functional consequence
   • Apparent stage-directionality contrasts with earlier mid-ring downregulation and is not reconciled

• It remains unknown how Sir2B enzymatic deacetylation is mechanistically coupled to promoter-type-selective var silencing, and what molecular basis underlies its strain-dependent contribution.
• No direct substrate or interaction partner for Sir2B defined in the corpus
• Structural basis of promoter-type selectivity unresolved
• Genetic drivers of strain-background dependence not identified